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Tuesday, March 3, 2015

March 2015

Alzheimer’s Protein Found in Young Brains for the First Time

Brain Journal

The mechanisms that contribute to selective vulnerability of the magnocellular basal forebrain cholinergic neurons in neurodegenerative diseases, such as Alzheimer’s disease, are not fully understood. Because age is the primary risk factor for Alzheimer’s disease, mechanisms of interest must include age-related alterations in protein expression, cell type-specific markers and pathology. The present study explored the extent and characteristics of intraneuronal amyloid-β accumulation, particularly of the fibrillogenic 42-amino acid isoform, within basal forebrain cholinergic neurons in normal young, normal aged and Alzheimer’s disease brains as a potential contributor to the selective vulnerability of these neurons using immunohistochemistry and western blot analysis. Amyloid-β1–42 immunoreactivity was observed in the entire cholinergic neuronal population regardless of age or Alzheimer’s disease diagnosis. The magnitude of this accumulation as revealed by optical density measures was significantly greater than that in cortical pyramidal neurons, and magnocellular neurons in the globus pallidus did not demonstrate a similar extent of amyloid immunoreactivity. Immunoblot analysis with a panel of amyloid-β antibodies confirmed accumulation of high concentration of amyloid-β in basal forebrain early in adult life. There was no age- or Alzheimer-related alteration in total amyloid-β content within this region. In contrast, an increase in the large molecular weight soluble oligomer species was observed with a highly oligomer-specific antibody in aged and Alzheimer brains when compared with the young. Similarly, intermediate molecular weight oligomeric species displayed an increase in aged and Alzheimer brains when compared with the young using two amyloid-β42 antibodies. Compared to cortical homogenates, small molecular weight oligomeric species were lower and intermediate species were enriched in basal forebrain in ageing and Alzheimer’s disease. Regional and age-related differences in accumulation were not the result of alterations in expression of the amyloid precursor protein, as confirmed by both immunostaining and western blot. Our results demonstrate that intraneuronal amyloid-β accumulation is a relatively selective trait of basal forebrain cholinergic neurons early in adult life, and increases in the prevalence of intermediate and large oligomeric assembly states are associated with both ageing and Alzheimer’s disease. Selective intraneuronal amyloid-β accumulation in adult life and oligomerization during the ageing process are potential contributors to the degeneration of basal forebrain cholinergic neurons in Alzheimer’s disease.


Resveratrol Prevents Age-Related Memory and Mood Dysfunction with Increased Hippocampal Neurogenesis and Microvasculature

Nature Scientific Reports

Greatly waned neurogenesis, diminished microvasculature, astrocyte hypertrophy and activated microglia are among the most conspicuous structural changes in the aged hippocampus. Because these alterations can contribute to age-related memory and mood impairments, strategies efficacious for mitigating these changes may preserve cognitive and mood function in old age. Resveratrol, a phytoalexin found in the skin of red grapes having angiogenic and antiinflammatory properties, appears ideal for easing these age-related changes. Hence, we examined the efficacy of resveratrol for counteracting age-related memory and mood impairments and the associated detrimental changes in the hippocampus. Two groups of male F344 rats in late middle-age having similar learning and memory abilities were chosen and treated with resveratrol or vehicle for four weeks. Analyses at ~25 months of age uncovered improved learning, memory and mood function in resveratrol-treated animals but impairments in vehicle-treated animals. Resveratrol-treated animals also displayed increased net neurogenesis and microvasculature, and diminished astrocyte hypertrophy and microglial activation in the hippocampus. These results provide novel evidence that resveratrol treatment in late middle age is efficacious for improving memory and mood function in old age. Modulation of the hippocampus plasticity and suppression of chronic low-level inflammation appear to underlie the functional benefits mediated by resveratrol.


Multimodal Analysis of Antipsychotic Effects on Brain Structure and Function in First-Episode Schizophrenia

JAMA Psychiatry


Recent data suggest that treatment with antipsychotics is associated with reductions in cortical gray matter in patients with schizophrenia. These findings have led to concerns about the effect of antipsychotic treatment on brain structure and function; however, no studies to date have measured cortical function directly in individuals with schizophrenia and shown antipsychotic-related reductions of gray matter.

To examine the effects of antipsychotics on brain structure and function in patients with first-episode schizophrenia, using cortical thickness measurements and administration of the AX version of the Continuous Performance Task (AX-CPT) during event-related functional magnetic resonance imaging.

Design, Setting, and Participants 
This case-control cross-sectional study was conducted at the Imaging Research Center of the University of California, Davis, from November 2004 through July 2012. Participants were recruited on admission into the Early Diagnosis and Preventive Treatment Clinic, an outpatient clinic specializing in first-episode psychosis. Patients with first-episode schizophrenia who received atypical antipsychotics (medicated patient group) (n = 23) and those who received no antipsychotics (unmedicated patient group) (n = 22) and healthy control participants (n = 37) underwent functional magnetic resonance imaging using a 1.5-T scanner.

Main Outcomes and Measures 
Behavioral performance was measured by trial accuracy, reaction time, and d′-context score. Voxelwise statistical parametric maps tested differences in functional activity during the AX-CPT, and vertexwise maps of cortical thickness tested differences in cortical thickness across the whole brain.

Significant cortical thinning was identified in the medicated patient group relative to the control group in prefrontal (mean reduction [MR], 0.27 mm; P < .001), temporal (MR, 0.34 mm; P = .02), parietal (MR, 0.21 mm; P = .001), and occipital (MR, 0.24 mm; P = .001) cortices. The unmedicated patient group showed no significant cortical thickness differences from the control group after clusterwise correction. The medicated patient group showed thinner cortex compared with the unmedicated patient group in the dorsolateral prefrontal cortex (DLPFC) (MR, 0.26 mm; P = .001) and temporal cortex (MR, 0.33 mm; P = .047). During the AX-CPT, both patient groups showed reduced DLPFC activity compared with the control group (P = .02 compared with the medicated group and P < .001 compared with the unmedicated group). However, the medicated patient group demonstrated higher DLPFC activation (P = .02) and better behavioral performance (P = .02) than the unmedicated patient group.

Conclusions and Relevance 
These findings highlight the complex relationship between antipsychotic treatment and the structural, functional, and behavioral deficits repeatedly identified in schizophrenia. Although short-term treatment with antipsychotics was associated with prefrontal cortical thinning, treatment was also associated with better cognitive control and increased prefrontal functional activity. This study adds important context to the growing literature on the effects of antipsychotics on the brain and suggests caution in interpreting neuroanatomical changes as being related to a potentially adverse effect on brain function.


Study seeks to refine prescribing through genetics 

Pittsburgh Post-Gazette

The University of Pittsburgh Graduate School of Public Health will participate in a study that could hasten the day when a patient’s genetic profile, not trial and error, helps a doctor determine which medications to prescribe.

Genetic factors determine how a patient responds to a medication. A person may get better results from one drug than another. People also metabolize drugs at different rates, so some require smaller doses than others. 

The 28-month, $350,000 study will enroll about 400 volunteers with mental-health disorders who are clients of NHS Human Services in Allegheny, Beaver, Dauphin and Lehigh counties. The study is funded by the Polk Foundation, Downtown.

Researchers will analyze genetic material from about half of the volunteers and use those insights to make medication adjustments aimed at optimizing drug performance and decreasing side effects and adverse drug interactions, said Dietrich Stephan, professor and chairman of Pitt’s Department of Human Genetics, who will head the study’s clinical advisory panel.

The other volunteers, serving as a control group, will receive their usual care.

The researchers foresee a time when doctors routinely consult a patient’s genetic profile to select medications and determine the correct dosage. While that’s already done with certain cancer patients, standard practice is for a doctor to prescribe a medication and, if it yields inadequate results or produces intolerable side effects, change the dose or switch to another drug.

“It’s an inefficient process,” Mr. Stephan said.

Most drugs work correctly in only about half of the people who take them, said Michael Christman, president and CEO of Coriell Institute for Medical Research in Camden, N.J. The institute’s for-profit arm, Coriell Life Sciences, is providing genetic testing and interpretation for the study.

If a drug fails to work, treatment is delayed, said Kevin Bain, vice president of medication risk mitigation at CareKinesis Inc., the Moorestown, N.J., firm providing analysis for the study.

Side effects and adverse drug interactions pose additional risks. Mr. Stephan said one group of researchers found that 1 million people are hospitalized annually because of adverse drug interactions and that as many as 106,000 of them die.

Mr. Stephan said the coming study focuses on patients with mental-health disorders because they take multiple medications, rendering them especially vulnerable to adverse reactions. He envisions a second study focusing on the elderly, another vulnerable group.

Deb Burock, senior corporate director of NHS Human Services, said her agency is participating because of the “potential to really improve the quality of life of the people that we serve ... We want to find a more effective means of supporting these individuals.”  Kim Sonafelt, who oversees the agency’s programs in various counties, said clients in Allegheny and Beaver counties take an average of 10 medications each.

The falling cost of genetic testing and medicine’s increasing focus on personalized medicine support a genetics-based approach to medication management, said Mr. Christman and Scott Megill, president and CEO of Coriell Life Sciences. Tests costs $500 or less, Mr. Megill said, with Medicare and some private insurers providing coverage.

The research “is definitely needed,” said Kathi Elliott, a psychiatric nurse practitioner at Adaptive Behavioral Services in East Liberty, who struggles to “tease out” the most appropriate medications and doses for patients presenting complex symptoms. She is not involved in the study.

Ms. Elliott, who has a doctor of nursing practice degree, said she uses a thorough patient assessment, including family history with psychiatric drugs, to help narrow medication choices. Because many people are reluctant to seek help for mental-health issues, she said, she worries about discouraging patients if medications don’t work as expected.

Kirstyn Kameg, professor of nursing and coordinator of the psychiatric mental health nurse practitioner program at Robert Morris University, said psychiatric medications may cause fatigue, anxiety, sexual problems or other issues. A person who has a bad experience, she said, may withdraw from treatment.

“You may lose them as a patient,” said Ms. Kameg, who is not involved in the study.


Anticholinergic Drugs Linked to Higher Dementia Risk

JAMA Internal Medicine


Many medications have anticholinergic effects. In general, anticholinergic-induced cognitive impairment is considered reversible on discontinuation of anticholinergic therapy. However, a few studies suggest that anticholinergics may be associated with an increased risk for dementia.

To examine whether cumulative anticholinergic use is associated with a higher risk for incident dementia.

Design, Setting, and Participants 
Prospective population-based cohort study using data from the Adult Changes in Thought study in Group Health, an integrated health care delivery system in Seattle, Washington. We included 3434 participants 65 years or older with no dementia at study entry. Initial recruitment occurred from 1994 through 1996 and from 2000 through 2003. Beginning in 2004, continuous replacement for deaths occurred. All participants were followed up every 2 years. Data through September 30, 2012, were included in these analyses.

Computerized pharmacy dispensing data were used to ascertain cumulative anticholinergic exposure, which was defined as the total standardized daily doses (TSDDs) dispensed in the past 10 years. The most recent 12 months of use was excluded to avoid use related to prodromal symptoms. Cumulative exposure was updated as participants were followed up over time.

Main Outcomes and Measures 
Incident dementia and Alzheimer disease using standard diagnostic criteria. Statistical analysis used Cox proportional hazards regression models adjusted for demographic characteristics, health behaviors, and health status, including comorbidities.

The most common anticholinergic classes used were tricyclic antidepressants, first-generation antihistamines, and bladder antimuscarinics. During a mean follow-up of 7.3 years, 797 participants (23.2%) developed dementia (637 of these [79.9%] developed Alzheimer disease). A 10-year cumulative dose-response relationship was observed for dementia and Alzheimer disease (test for trend, P < .001). For dementia, adjusted hazard ratios for cumulative anticholinergic use compared with nonuse were 0.92 (95% CI, 0.74-1.16) for TSDDs of 1 to 90; 1.19 (95% CI, 0.94-1.51) for TSDDs of 91 to 365; 1.23 (95% CI, 0.94-1.62) for TSDDs of 366 to 1095; and 1.54 (95% CI, 1.21-1.96) for TSDDs greater than 1095. A similar pattern of results was noted for Alzheimer disease. Results were robust in secondary, sensitivity, and post hoc analyses.

Conclusions and Relevance 
Higher cumulative anticholinergic use is associated with an increased risk for dementia. Efforts to increase awareness among health care professionals and older adults about this potential medication-related risk are important to minimize anticholinergic use over time.


Microbiome and Neuroscience: The Mind-bending Power of Bacteria

The Kavli Foundation 

Our microbes, especially those living in the gut, have a powerful influence on the brain, influencing our emotions, our thoughts and even our memory. On January 15, a microbiologist and a neuroscientist will discuss the emerging science of the human microbiome, which is more intimately linked to human health than ever imagined.

In fact, evidence accumulated in the last five to 10 years shows that these microbes, which predominantly live in the gastrointestinal tract, shape the development and function of the brain. They influence a range of complex human behaviors, including learning and memory, mood and emotion, and appetite and satiety. They have also been linked to disorders of the central nervous system including anxiety, depression, autism and multiple sclerosis, which may be a consequence of an ecosystem that has fallen out of balance.

Three researchers at the forefront of research on the microbiome-brain connection recently spoke with The Kavli Foundation about how microbes communicate with the brain and whether we can modify the gut microbiome to treat disorders of the brain and mind.


Premature Babies at Greater Risk of Mental Health Disorders as Adults



To determine the risk for psychiatric disorders among extremely low birth weight (ELBW) survivors in their early to mid-30s and to determine whether those born small for gestational age or those exposed to a full course of antenatal corticosteroids (ACS) were at particularly high risk.

A prospective, longitudinal, population-based cohort of 84 ELBW survivors and 90 normal birth weight (NBW) control participants born in Ontario, Canada from 1977 to 1982 were assessed by interviewers naive to birth weight status using the Mini-International Neuropsychiatric Interview.

ELBW survivors had lower odds of an alcohol or substance use disorder but higher odds of current non–substance-related psychiatric problems (odds ratio [OR] = 2.47; 95% confidence interval [CI], 1.19–5.14). Those born ELBW and SGA exhibited the same patterns with larger effects. ACS-exposed ELBW survivors had even higher odds of any current non–substance-related psychiatric disorder (OR = 4.41; 95% CI, 1.65–11.82), particularly generalized anxiety disorder (OR = 3.42; 95% CI, 1.06–11.06), the generalized type of social phobia (OR = 5.80; 95% CI, 1.20–27.99), and the inattentive subtype of attention-deficit/hyperactivity disorder (OR = 11.45; 95% CI, 2.06–63.50).

In their early to mid-30s, ELBW survivors were less likely to have alcohol or substance use disorders but may be at greater risk for other psychiatric problems. Those exposed to ACS were at especially high risk and manifested no reduction in alcohol or substance use disorders. ELBW survivors exposed to ACS may be a special group at risk for psychopathology in adulthood.


Chronic-Fatigue Syndrome Is Real and Is Now Called Systemic-Exertion-Intolerance Disease (SEID)

The New York Times

The Institute of Medicine on Tuesday proposed a new name and new diagnostic criteria for the condition that many still call chronic fatigue syndrome.

Experts generally agree that the disease has a physical basis, but they have struggled for decades to characterize its symptoms. The new report may help improve diagnosis, but the recommendations are unlikely to end the long, contentious debate over who has the condition and what may be causing it.

An institute panel recommended that the illness be renamed “systemic exertion intolerance disease,” a term that reflects what patients, clinicians and researchers all agree is a core symptom: a sustained depletion of energy after minimal activity, called postexertional malaise.

The new name “really describes much more directly the key feature of the illness, which is the inability to tolerate both physical and cognitive exertion,” said Dr. Peter Rowe, a member of the panel and a pediatrician at Johns Hopkins who treats children with the condition.

An alternate name for the illness, myalgic encephalomyelitis, meaning “brain and spinal cord inflammation with muscle pain,” was coined decades ago. Many experts now refer to the condition as M.E./C.F.S.

About one million people in the United States are believed to have the syndrome. Many say they have been accused of imagining or exaggerating their symptoms, and many doctors have long viewed it as a psychological illness.

The authors urged that doctors take patients’ physical complaints seriously. “This is not a figment of their imagination,” said Dr. Ellen Wright Clayton, the chairwoman of the Institute of Medicine panel and a professor of pediatrics and law at Vanderbilt University.

Patients attribute much of their mistreatment to the name “chronic fatigue syndrome,” chosen by the Centers for Disease Control in 1988.

“We wanted to move it away from this label that often elicits very trite comments, possibly intended to be humorous, like ‘I’m tired, I must have that too,’ ” Dr. Rowe said. “Everybody’s had some experience of fatigue, but this is so much more than that.”

Leonard A. Jason, a psychology professor at DePaul University in Chicago and an expert on the illness, predicted that patients would be reluctant to accept the new name.

“The committee has come up with a name without vetting it,” Dr. Jason said. “And they will basically get a tremendous amount of discontent and dissatisfaction right from the starting point, because the patients want something very different.”

Many strongly prefer myalgic encephalomyelitis, because it underscores a physical basis for the condition. But the authors of the new report said that myalgic encephalomyelitis “does not accurately describe the major features of the disease.”

Although some research has suggested that inflammation of the central nervous system is involved, its role is not proven, and muscle pain is not as prominent as other features.

Most patients develop the syndrome after contracting a cold, flu or other viral illness, but other environmental or toxic exposures may act as triggers. Although no cause has been identified, people with the illness may suffer neurological, hormonal and immunological impairments.

The new diagnostic criteria include six months of profound, unexplained fatigue and postexertional malaise, as well as a third key symptom: unrefreshing sleep. Patients must also exhibit cognitive problems or “orthostatic intolerance,” an inability to stand upright for more than a short period.

“We are hoping they provide a very clear path for clinicians to make a diagnosis,” said Dr. Lucinda Bateman, a panel member from Salt Lake City. “We want to make sure that symptoms that maybe have been overlooked by clinicians have been put front and center.”

Developing diagnostic criteria is easiest when medical tests can be used, as with HIV or hepatitis C, and much harder when an illness must be defined by its symptoms. Researchers and clinicians have developed at least 20 different definitions over the years for the condition.

The most commonly used has been the C.D.C.’s definition, but many researchers and clinicians complain that those criteria identify many patients who more likely are suffering from depression and other conditions that can cause prolonged fatigue.

The new report is one of two studies that have been the focus of intense debate among patients with the condition. The National Institutes of Health is currently revising a draft report about research priorities for the illness.

Patients have criticized both efforts. Although the 15 members on the Institute of Medicine panel included some clinicians with strong experience in treating patients with the condition, a majority were not known to have any expertise in the illness.

In recent years, the National Institutes of Health has spent around $5 million a year on research for the condition, far less than patient advocates would like.


Direct Link Between ADHD and Premature Death

The Lancet


Attention deficit hyperactivity disorder (ADHD) is a common mental disorder associated with factors that are likely to increase mortality, such as oppositional defiant disorder or conduct disorder, criminality, accidents, and substance misuse. However, whether ADHD itself is associated with increased mortality remains unknown. We aimed to assess ADHD-related mortality in a large cohort of Danish individuals.

By use of the Danish national registers, we followed up 1·92 million individuals, including 32 061 with ADHD, from their first birthday through to 2013. We estimated mortality rate ratios (MRRs), adjusted for calendar year, age, sex, family history of psychiatric disorders, maternal and paternal age, and parental educational and employment status, by Poisson regression, to compare individuals with and without ADHD.

During follow-up (24·9 million person-years), 5580 cohort members died. The mortality rate per 10 000 person-years was 5·85 among individuals with ADHD compared with 2·21 in those without (corresponding to a fully adjusted MRR of 2·07, 95% CI 1·70–2·50; p<0·0001). Accidents were the most common cause of death. Compared with individuals without ADHD, the fully adjusted MRR for individuals diagnosed with ADHD at ages younger than 6 years was 1·86 (95% CI 0·93–3·27), and it was 1·58 (1·21–2·03) for those aged 6–17 years, and 4·25 (3·05–5·78) for those aged 18 years or older. After exclusion of individuals with oppositional defiant disorder, conduct disorder, and substance use disorder, ADHD remained associated with increased mortality (fully adjusted MRR 1·50, 1·11–1·98), and was higher in girls and women (2·85, 1·56–4·71) than in boys and men (1·27, 0·89–1·76).

ADHD was associated with significantly increased mortality rates. People diagnosed with ADHD in adulthood had a higher MRR than did those diagnosed in childhood and adolescence. Comorbid oppositional defiant disorder, conduct disorder, and substance use disorder increased the MRR even further. However, when adjusted for these comorbidities, ADHD remained associated with excess mortality, with higher MRRs in girls and women with ADHD than in boys and men with ADHD. The excess mortality in ADHD was mainly driven by deaths from unnatural causes, especially accidents.


People With Mental Health Disorders May Die At Younger Ages

JAMA Psychiatry


Despite the potential importance of understanding excess mortality among people with mental disorders, no comprehensive meta-analyses have been conducted quantifying mortality across mental disorders.

To conduct a systematic review and meta-analysis of mortality among people with mental disorders and examine differences in mortality risks by type of death, diagnosis, and study characteristics.

Data Sources 
We searched EMBASE, MEDLINE, PsychINFO, and Web of Science from inception through May 7, 2014, including references of eligible articles. Our search strategy included terms for mental disorders (eg, mental disorders, serious mental illness, and severe mental illness), specific diagnoses (eg, schizophrenia, depression, anxiety, and bipolar disorder), and mortality. We also used Google Scholar to identify articles that cited eligible articles.

Study Selection 
English-language cohort studies that reported a mortality estimate of mental disorders compared with a general population or controls from the same study setting without mental illness were included. Two reviewers independently reviewed the titles, abstracts, and articles. Of 2481 studies identified, 203 articles met the eligibility criteria and represented 29 countries in 6 continents.

Data Extraction and Synthesis 
One reviewer conducted a full abstraction of all data, and 2 reviewers verified accuracy.

Main Outcomes and Measures 
Mortality estimates (eg, standardized mortality ratios, relative risks, hazard ratios, odds ratios, and years of potential life lost) comparing people with mental disorders and the general population or people without mental disorders. We used random-effects meta-analysis models to pool mortality ratios for all, natural, and unnatural causes of death. We also examined years of potential life lost and estimated the population attributable risk of mortality due to mental disorders.

For all-cause mortality, the pooled relative risk of mortality among those with mental disorders (from 148 studies) was 2.22 (95% CI, 2.12-2.33). Of these, 135 studies revealed that mortality was significantly higher among people with mental disorders than among the comparison population. A total of 67.3% of deaths among people with mental disorders were due to natural causes, 17.5% to unnatural causes, and the remainder to other or unknown causes. The median years of potential life lost was 10 years (n = 24 studies). We estimate that 14.3% of deaths worldwide, or approximately 8 million deaths each year, are attributable to mental disorders.

Conclusions and Relevance 
These estimates suggest that mental disorders rank among the most substantial causes of death worldwide. Efforts to quantify and address the global burden of illness need to better consider the role of mental disorders in preventable mortality.


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