Economist Magazine Report on Human Genome

The Economist magazine has a great report on the human genome. Admittedly, it’s challenging reading much of the time.

Many of us following the PSP/CBD genetics project will be familiar with the term GWAS – genome-wide association study. The genetics project is a GWAS taking place on brain tissue of confirmed PSP and CBD patients. This magazine report has a lot to say about the strengths and limitations of GWAS. One of the recent “discoveries” we learned about was that someone needs multiple genetic mutations to develop PSP or CBD; apparently this isn’t a finding specific to PSP or CBD.

Two other things I learned from this special report with regard to GWAS are:

“GWAS has not been a total failure. It has revealed lots of mutations of small effect. On average, though, these add up to only 10% of the total heritability of any given disease. Mendelian effects add about another 1%. The rest, in a phrase that geneticists have borrowed from physicists, is referred to as ‘dark matter’. These mutations appear to be tremendously important, yet neither Mendelian nor GWAS techniques can detect them. Mendelian mutations are noticed because they are rare and powerful. GWAS mutations are seen because, though puny, they are common. The dark matter lies in the middle: too rare for GWAS but not powerful enough to leave a clear Mendelian signal. Bigger GWAS, with more statistical power, may help a bit, but clearly new methods are needed. One will be to deploy whole-genome sequencing more widely, now that it is becoming so much cheaper.”

“It is one thing to find a gene in the genome; it is quite another to find out what it does; and another still to understand whether that knowledge has any medical value. Until these points are dealt with, the drugmaking machine that genomics once promised to become cannot be built.”

Here are links to the two most interesting articles in the report:

“Biology 2.0”
www.economist.com/node/16349358

“Marathon man”
www.economist.com/node/16349422

Robin

Hospital Delirium: one-third of those over 70 (NYT)

This New York Times article is on hospital delirium, which affects one-third of hospital patients over 70.
Some excerpts:

“The cause of delirium is unclear, but there are many apparent triggers: infections, surgery, pneumonia, and procedures like catheter insertions, all of which can spur anxiety in frail, vulnerable patients. Some medications, difficult for older people to metabolize, seem associated with delirium.”

“But new research shows significant negative effects.  Even short episodes can hinder recovery from patients’ initial conditions, extending hospitalizations, delaying scheduled procedures like surgery, requiring more time and attention from staff members and escalating health care costs. Afterward, patients are more often placed, whether temporarily or permanently, in nursing homes or rehabilitation centers. Older delirium sufferers are more likely to develop dementia later. And, Dr. Inouye found, 35 percent to 40 percent die within a year.”

“Dr. Malaz A. Boustani…found that elderly patients experiencing delirium were hospitalized six days longer, and placed in nursing homes 75 percent of the time, five times as often as those without delirium. Nearly one-tenth died within a month. Experts say delirium can contribute to death by weakening patients or leading to complications like pneumonia or blood clots.”

Here’s a link to the full article:

www.nytimes.com/2010/06/21/science/21delirium.html

Hallucinations in Hospital Pose Risk to Elderly
New York Times
By Pam Belluck
June 20, 2010

Clearly we need to have more effort in hospitals to prevent delirium!

Robin

 

Hospital Delirium: one-third of those over 70; negative

This New York Times article is on hospital delirium, which affects one-third of patients over 70.

Some excerpts:

“The cause of delirium is unclear, but there are many apparent triggers: infections, surgery, pneumonia, and procedures like catheter insertions, all of which can spur anxiety in frail, vulnerable patients. Some medications, difficult for older people to metabolize, seem associated with delirium.”

“But new research shows significant negative effects. Even short episodes can hinder recovery from patients’ initial conditions, extending hospitalizations, delaying scheduled procedures like surgery, requiring more time and attention from staff members and escalating health care costs. Afterward, patients are more often placed, whether temporarily or permanently, in nursing homes or rehabilitation centers. Older delirium sufferers are more likely to develop dementia later. And, Dr. Inouye found, 35 percent to 40 percent die within a year.”

“Dr. Malaz A. Boustani…found that elderly patients experiencing delirium were hospitalized six days longer, and placed in nursing homes 75 percent of the time, five times as often as those without delirium. Nearly one-tenth died within a month. Experts say delirium can contribute to death by weakening patients or leading to complications like pneumonia or blood clots.”

Here’s the full article.

http://www.nytimes.com/2010/06/21/scien … irium.html

June 20, 2010
Hallucinations in Hospital Pose Risk to Elderly
By Pam Belluck
New York Times

No one who knows Justin Kaplan would ever have expected this. A Pulitzer Prize-winning historian with a razor intellect, Mr. Kaplan, 84, became profoundly delirious while hospitalized for pneumonia last year. For hours in the hospital, he said, he imagined despotic aliens, and he struck a nurse and threatened to kill his wife and daughter.

“Thousands of tiny little creatures,” he said, “some on horseback, waving arms, carrying weapons like some grand Renaissance battle,” were trying to turn people “into zombies.” Their leader was a woman “with no mouth but a very precisely cut hole in her throat.”

Attacking the group’s “television production studio,” Mr. Kaplan fell from his hospital bed, cutting himself and “sliding across the floor on my own blood,” he said. The hospital called security because “a nurse was trying to restrain me and I repaid her with a kick.”

Mr. Kaplan’s hallucinations lifted as doctors treated his pneumonia. But hospitals say many patients are experiencing such inexplicable disorienting episodes. Doctors call it “hospital delirium,” and are increasingly trying to prevent or treat it.

Disproportionately affecting older people, a rapidly growing share of patients, hospital delirium affects about one-third of patients over 70, and a greater percentage of intensive-care or postsurgical patients, the American Geriatrics Society estimates.

“A delirious patient happens almost every day,” said Dr. Manuel N. Pacheco, director of consultation and emergency services at Mount Auburn Hospital in Cambridge, Mass. He treated Mr. Kaplan, whom he described as “a very learned, acclaimed person,” for whom “this is not the kind of behavior that’s normal.” “People don’t talk about it, because it’s embarrassing,” Dr. Pacheco said. “They’re having sheer terror, like their worst nightmare.”

The cause of delirium is unclear, but there are many apparent triggers: infections, surgery, pneumonia, and procedures like catheter insertions, all of which can spur anxiety in frail, vulnerable patients. Some medications, difficult for older people to metabolize, seem associated with delirium.

Doctors once dismissed it as a “reversible transient phenomenon,” thinking “it’s O.K. for someone, if they’re elderly, to become confused in the hospital,” said Dr. Sharon Inouye, a Harvard Medical School professor. But new research shows significant negative effects.

Even short episodes can hinder recovery from patients’ initial conditions, extending hospitalizations, delaying scheduled procedures like surgery, requiring more time and attention from staff members and escalating health care costs. Afterward, patients are more often placed, whether temporarily or permanently, in nursing homes or rehabilitation centers. Older delirium sufferers are more likely to develop dementia later. And, Dr. Inouye found, 35 percent to 40 percent die within a year.

“It’s terrible, more dangerous than a fall,” said Dr. Malaz A. Boustani, a professor at the Indiana University Center for Aging Research, who found that elderly patients experiencing delirium were hospitalized six days longer, and placed in nursing homes 75 percent of the time, five times as often as those without delirium. Nearly one-tenth died within a month. Experts say delirium can contribute to death by weakening patients or leading to complications like pneumonia or blood clots.

Ethel Reynolds, 75, entered a Virginia hospital last July to have fluid drained that had been causing her feet to swell. She wound up hospitalized for weeks, sometimes so delirious that “she screamed constantly, writhed,” said her daughter, Susan Byrd. “I had to get in bed with her because she thought someone was coming and they were going to hurt us,” Ms. Byrd said.

Ms. Reynolds ended up needing dialysis and surgery after an infection, and she died in September.

“We got her death certificate, and the No. 1 cause of death was delirium,” said Ms. Byrd, an ophthalmology nurse. “I was just blown away. As a nurse, I was expecting a quote-unquote medical reason: kidneys, heart, lung, an organ that I could understand had failed, and it wasn’t. It was delirium.”

Other triggers involve disorienting changes: sleep interrupted for tests, isolation, changing rooms, being without eyeglasses or dentures. Medication triggers can include some antihistamines, sleeping pills, antidepressants and drugs for nausea and ulcers. Dr. Inouye said that many “doctors don’t know how to appropriately use meds in older people, in terms of dosing” and compatibility with other medications.

Earle Helton, 80, a retired chemist hospitalized after a stroke, ordered his family to “throw a rope over the hedge so he could escape,” said his daughter, Amanda. He tried removing his hospital gown, loudly sang “Lullaby and Goodnight,” and doctors had to tie down his hands to prevent him from leaving, said his wife, Ginnie. Only when Dr. Inouye stopped some medications that other doctors had prescribed did he become lucid.

Delirium is sometimes treated with antipsychotics, but doctors urge caution using such drugs.

Delirium can wax and wane, not always causing aggressive agitation.

“It is often the person quietly in bed,” and the condition can linger for weeks or months, landing patients back in the hospital, said Dr. Julie Moran, a geriatrician at Beth Israel Deaconess Medical Center in Boston. “We would have to build 100 more floors to keep everybody until they cleared their delirium. There are times when we could be working round the clock seeing patients with delirium.”

Frequently, geriatricians say, delirium is misdiagnosed, or described on patient charts as agitation, confusion or inappropriate behavior, so subsequent doctors might not realize the problem. One study found “delirium” used in only 7 percent of cases; “confusion” was most common. Another study of delirious older emergency-room patients found that the condition was missed in three-quarters of them.

People with dementia seem at greater risk for delirium, but many delirious patients have no dementia. For some of them, delirium increases the risk of later dementia. In such cases, it is unclear if delirium caused the dementia, or was simply a signal that the person would develop it later.

Some hospitals are adopting delirium-prevention programs, including one developed by Dr. Inouye, which adjusts schedules, light and noise to help patients sleep, ensures that patients have their eyeglasses and hearing aids, and has them walk, exercise and do cognitive activities like word games.

Dr. Moran’s hospital removes catheters, intravenous lines and other equipment whenever possible because they can make patients feel trapped, leading to delirium. She said nurses repeatedly assess cognitive function so patients “don’t have smoldering symptoms of delirium for days before they end up yelling and screaming.”

Mr. Kaplan, a biographer of Mark Twain and Walt Whitman, later jotted notes about his hallucinations, including being in a police helicopter “tracking fugitives with enormous light.”

“Exhilarating until I become one of the fugitives,” he wrote. “End up cold and naked in some sort of subway passage.”

His fall bruised his elbow, leg and wrist, said his wife, the writer Anne Bernays. The next day, “he was gaga till about noon,” and even “looked me in the eye and said ‘I’m going to kill you,’ ” she said. “He didn’t know where he was and didn’t recognize me.”

Fortunately, his delirium was discovered very quickly and he made a very good recovery, Dr. Pacheco said. “But,” he said, “delirium is very disruptive for the patient, family, hospital caregivers.”

As Mr. Kaplan understated later, “It was a lot of unpleasantness.”

Cholinergic deficits in PSP, CBS, etc

In this Japanese PET study, acetylcholinesterase activity in the brain was measured in seven CBS patients, 12 PSP patients, and 8 FTD (frontotemporal dementia) patients.

Acetylcholine is a neurotransmitter that helps with cognition. By measuring “acetylcholinesterase activity, we can assess the integrity of the…cholinergic system.”

“Cerebral cortical acetylcholinesterase activity was moderately reduced in corticobasal syndrome and mildly reduced in progressive supranuclear palsy, while thalamic acetylcholinesterase activity was remarkably reduced only in progressive supranuclear palsy.”

The FTD group showed no decline in acetylcholinesterase activity. The authors make the point that acetylcholinesterase inhibitors (AChEIs include Aricept, Exelon, and Razadyne) are of no value in FTD.

The authors “found a correlation between MMSE scores and cortical acetylcholinesterase activity in the corticobasal syndrome group, suggesting that cognitive decline might be caused by cholinergic dysfunction in corticobasal syndrome.” From those in our local support group and on the CBD-related Yahoo!Group, it seems that AChEIs are of limited value in CBS.

Anecdotal evidence also indicates that AChEIs are of limited value in PSP. Further, the authors note: “In spite of the mounting evidence of cholinergic impairment in the brain of patients with progressive supranuclear palsy, a number of drug trial studies have failed to show beneficial effects of cholinergic stimulant therapy. … Other forms of acetylcholine modulating agent might be helpful for improving clinical symptoms in patients with progressive supranuclear palsy.” I’m not sure what “other forms” includes.

The authors compare the cholinergic deficits in CBS and PSP to those with Alzheimer’s Disease and other disorders. “We have studied brain acetylcholinesterase activity in other neurodegenerative diseases by PET and found that mean reduction of cortical acetylcholinesterase activity, compared with normal controls, was 13% in mild to moderate late-onset Alzheimer’s disease, 23% in mild to moderate early-onset Alzheimer’s disease, 12% in Parkinson’s disease without dementia, 27% in Parkinson’s disease with dementia and dementia with Lewy bodies, 21 and 36% in two patients with N279K FTDP-17 and 6% in a cerebellar variant of multiple system atrophy. Compared with the reduction of cortical acetylcholinesterase activities in these disorders, the reduction of cortical acetylcholinesterase was moderate [17.5%] in corticobasal syndrome and mild [9.4%] in progressive supranuclear palsy.”

I’ve copied the abstract below.

Robin

Brain. 2010 Jun 17. [Epub ahead of print]

Cholinergic imaging in corticobasal syndrome, progressive supranuclear palsy and frontotemporal dementia.

Hirano S, Shinotoh H, Shimada H, Aotsuka A, Tanaka N, Ota T, Sato K, Ito H, Kuwabara S, Fukushi K, Irie T, Suhara T.
Molecular Neuroimaging Group, Molecular Imaging Centre, National Institute of Radiological Sciences, Chiba, Japan.

Abstract
Corticobasal syndrome, progressive supranuclear palsy and frontotemporal dementia are all part of a disease spectrum that includes common cognitive impairment and movement disorders. The aim of this study was to characterize brain cholinergic deficits in these disorders.

We measured brain acetylcholinesterase activity by [(11)C] N-methylpiperidin-4-yl acetate and positron emission tomography in seven patients with corticobasal syndrome (67.6 +/- 5.9 years), 12 with progressive supranuclear palsy (68.5 +/- 4.1 years), eight with frontotemporal dementia (59.8 +/- 6.9 years) and 16 healthy controls (61.2 +/- 8.5 years).

Two-tissue compartment three-parameter model and non-linear least squares analysis with arterial input function were performed. k(3) value, an index of acetylcholinesterase activity, was calculated voxel-by-voxel in the brain of each subject. The k(3) images in each disease group were compared with the control group by using Statistical Parametric Mapping 2. Volume of interest analysis was performed on spatially normalized k(3) images.

The corticobasal syndrome group showed decreased acetylcholinesterase activity (k(3) values) in the paracentral region, frontal, parietal and occipital cortices (P < 0.05, cluster corrected).

The group with progressive supranuclear palsy had reduced acetylcholinesterase activity in the paracentral region and thalamus (P < 0.05, cluster corrected).

The frontotemporal dementia group showed no significant differences in acetylcholinesterase activity.

Volume of interest analysis showed mean cortical acetylcholinesterase activity to be reduced by 17.5% in corticobasal syndrome (P < 0.001), 9.4% in progressive supranuclear palsy (P < 0.05) and 4.4% in frontotemporal dementia (non-significant), when compared with the control group. Thalamic acetylcholinesterase activity was reduced by 6.4% in corticobasal syndrome (non-significant), 24.0% in progressive supranuclear palsy (P < 0.03) and increased by 3.3% in frontotemporal dementia (non-significant).

Both corticobasal syndrome and progressive supranuclear palsy showed brain cholinergic deficits, but their distribution differed somewhat. Significant brain cholinergic deficits were not seen in frontotemporal dementia, which may explain the unresponsiveness of this condition to cholinergic modulation therapy.

PubMed ID#: 20558417 (see pubmed.gov for this abstract only)

Gastroparesis, Bowel Dysfunction, and Urinary Problems

The Parkinson’s Disease Foundation (pdf.org) recently published a fact sheet on gastrointestinal and urinary dysfunction in Parkinson’s.  Of course many of those in the Brain Support Network are coping with these same symptoms.

Topics discussed include:  gastroparesis (stomach problems), bowel dysfunction, and bladder and urinary difficulties.

Here’s a link to the fact sheet, written by Dr. Pfeiffer, a neurologist who specializes in non-motor symptoms:

www.pdf.org/pdf/fs_gastrointestinal_urinary_10.pdf

Gastrointestinal and Urinary Dysfunction
by Ronald F. Pfeiffer, MD
PDF Fact Sheet, 2010

Happy reading,
Robin