Where in brain PSP may start (Japanese research)

This article by Japanese researchers describes a 78-year-old woman with what looks like early PSP. Since the pathological changes were in the substantia nigra and the subthalamic nucleus in this woman, the authors suggest that this is where PSP starts in everyone. The SN plays a major role in movement. The SN is also affected in Parkinson’s Disease. Both the SN and the STN are parts of the basal ganglia.
Robin

Neuropathology. 2010 Jun 21. [Epub ahead of print]

Early-stage progressive supranuclear palsy with degenerative lesions confined to the subthalamic nucleus and substantia nigra.

Sakai K, Yamada M.
Department of Neurology, Noto General Hospital, Nanao, Japan.

Abstract
We describe a 78-year-old Japanese woman with early-stage progressive supranuclear palsy (PSP). She had a 3-week history of postural instability and gait disturbance. On examination, upper vertical gaze palsy, akinesia, hyperreflexia with pathological reflexes, hesitation, and postural instability were observed. Rigidity and resting tremors were not apparent. Brain MRI revealed atrophy of the frontotemporal lobes and dilatation of the third ventricle. A month later, she died of cerebral infarction. The total duration of her clinical course was approximately 2 months. The brain weighed 1180 g after fixation. Macroscopically, mild atrophy of the frontal lobes and mild depigmentation of the substantia nigra were observed. The conspicuous findings included degeneration confined to the subthalamic nucleus and substantia nigra and widespread but infrequent tau-positive neurofibrillary tangles/pretangles and glial fibrillary tangles (tuft-shaped astrocytes, coiled bodies and argyrophilic threads) in the brain. It has been reported that the most affected areas in PSP are the globus pallidus, subthalamic nucleus and substantia nigra. We suggest that degeneration in PSP would start with involvement of the substantia nigra and subthalamic nucleus.

PubMed ID#: 20573028

Using grape seed extract to treat PSP and CBD?

This article out of Mount Sinai School of Medicine reviews studies in lab animals of GSPE (grape seed-derived polyphenolic extracts) in the treatment of tauopathies such as PSP, CBD, and AD. My impression is that most of the studies reviewed were done by researchers at Mount Sinai School of Medicine!

The researchers note: “Recent studies from our laboratory reveal that grape seed-derived polyphenolic extracts (GSPE) potently prevent tau fibrillization into neurotoxic aggregates and therapeutically promote the dissociation of preformed tau aggregates.”

The abstract indicates that this research team “initiated a series of studies exploring the role of GSPE (Meganatural-Az® GSPE) as a potential novel botanical drug for the treatment of certain forms of tauopathies including PSP…”

You can find more information on this product from this website promoting it:
http://www.meganaturalbp.com/polyphenolics/
They say they have FDA GRAS status (generally recognized as safe). This simply means the FDA views the chemical as safe, not that the FDA has approved of it as a drug that can be used for certain medical conditions. The disclosure section of the article indicates: “Drs. Pasinetti, Wang and Ho are named inventors of a pending patent application filed by Mount Sinai School of Medicine (MSSM) for grape seed polyphenolic extract.”

I assumed GSPE was the same thing as resveratrol. According to the article, “no detectable resveratrol is found in Meganatural-Az® GSPE.”

I couldn’t glean much about the “series of studies” in PSP. I don’t know if these are all biochemistry studies done in petri dishes or studies using lab animals. Some human studies must be going on as well because the article says: “Tolerability and dose escalation studies in PSP subjects are presently underway in our Institution, and will provide fundamental information for the characterization of appropriate doses of Meganatural-Az® GSPE in the treatment of PSP.”

The authors state: “In conclusion, our studies tentatively support the hypothesis, for the first time, that certain forms of bioavailable polyphenolic compounds in Meganatural-Az® GSPE may promote tau anti-oligomerization activities in the brain, ultimately delaying clinical PSP onset, and possibly therapeutically attenuating the clinical progression of PSP and other tauopathies.”

If anyone looks into this further, please share!

Robin

Journal of Neurochemistry. 2010 Jun 20. [Epub ahead of print]

Development of a grape seed polyphenolic extract with anti-oligomeric activity as a novel treatment in progressive supranuclear palsy and other tauopathies.

Pasinetti GM, Ksiezak-Reding H, Santa-Maria I, Wang J, Ho L.
Center of Excellence for Novel Approaches to Neurodiagnostics and Neurotherapeutics, Brain Institute, Center of Excellence for Research in Complementary and Alternative Medicine in Alzheimer’s Disease, Department of Neurology, Mount Sinai School of Medicine, New York, NY.

Abstract
A diverse group of neurodegenerative diseases – including progressive supranuclear palsy (PSP), corticobasal degeneration (CBD) and Alzheimer’s disease (AD) among others, collectively referred to as tauopathies – are characterized by progressive, age-dependent intracellular formations of misfolded protein aggregates that play key roles in the initiation and progression of neuropathogenesis.

Recent studies from our laboratory reveal that grape seed-derived polyphenolic extracts (GSPE) potently prevent tau fibrillization into neurotoxic aggregates and therapeutically promote the dissociation of preformed tau aggregates (Ho et al., 2009).

Based on our extensive bioavailability, bioactivity and functional pre-clinical studies, combined with the safety of GSPE in laboratory animals and in humans, we initiated a series of studies exploring the role of GSPE (Meganatural-Az((R)) GSPE) as a potential novel botanical drug for the treatment of certain forms of tauopathies including PSP, a neurodegenerative disorder involving the accumulation and deposition of misfolded tau proteins in the brain characterized, in part, by abnormal intracellular tau inclusions in specific anatomical areas involving astrocytes, oligodendrocytes and neurons (Takahashi et al., 2002).

In this mini-review article, we discuss the biochemical characterization of GSPE in our laboratory and its potential preventative and therapeutic role in model systems of abnormal tau processing pertinent to PSP and related tauopathies.

PubMed ID#: 20569300 (see pubmed.gov for this abstract)

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.”