“Hard Choice for a Comfortable Death: Sedation” (NYT)

The New York Times (nytimes.org) seems to have a new series called “Months to Live,” where it address end-of-life issues.  An article for tomorrow’s paper is the first I’ve seen on the topic of sedating someone near death in the hopes that they die while sleeping.  We had one support group member who instructed both hospice and her husband to provide extensive sedation to her, and even spelled out what medication she wanted to be given (phenobarbitol and morphine).

I looked into this topic a couple of years ago as we were preparing for my father to be removed from a ventilator and feeding tube.  (Very fortunately for our family, Dad gave us the ultimate gift and died of a heart attack before we removed life support.)

Besides these two group member stories, I know little on this topic so was very interested in today’s article.  You can find the article here:

www.nytimes.com/2009/12/27/health/27sedation.html

Months to Live
Hard Choice for a Comfortable Death: Sedation
New York Times
By Anemona Hartocollis
December 27, 2009

This is a tough subject for many.

Bill’s great article on hospice

When CurePSP was the Society, it published at least twice Bill’s (104fm’s) article on hospice in the PSP Advocate (now called the CurePSP Magazine). I didn’t see that the article had been posted here on the Forum. Here it is.

http://psp.org/includes/downloads/1stissue2006.pdf –> See article on page 12

WHEN SHOULD HOSPICE BE CONTACTED FOR SOMEONE WITH PSP?

William Carroll, RN, CHPN
HealthCare Dimensions Hospice, The Dana Farber Cancer Institute, Boston, MA
The PSP Advocate, 2006

As a participant in the online discussion forum available at forum.psp.org, I have often been asked my opinion as to when is the apropriate time to contact hospice. I receive this question fairly often because of my background and current employment as a registered nurse working in Hospice for Healthcare Dimensions, a subsidiary of the
Dana Farber Cancer Institute. I also have a family member who has been diagnosed with PSP.

There are basically two separate Medicare benefit programs that may be available for people with PSP and their families. These include the Medicare Home Health Benefit and the Medicare Hospice Benefit. Many private insurances have guidelines for qualifying for their own programs, but quite often, they are virtually identical to those offered through Medicare. It is usually worthwhile to review the publications available from the insurer and then speak with the benefit administrator to see what is available.

Each of the two plans has separate criteria which need to be met in order to qualify for the program. For the Medicare Home Health Benefit there must be a need for skilled care (custodial care alone, such as would be provided by a nurse’s aide, generally would not qualify), and the patient must be home bound. In the case of the Medicare Hospice Benefit, both the admitting physician and the Hospice Medical Director must certify that they believe if the disease runs its normal course, the patient has a prognosis of six months or less.

With many diseases that have an unpredictable rate of progression, and PSP is definitely no exception, determining a six-month prognosis with any true accuracy is extremely difficult. In consideration of this, the Medicare Hospice Benefit provides for unlimited renewals. Basically, this means that provided the admission criteria is still met, a person could potentially be eligible to receive all the care and benefits that Hospice provides for well beyond the original six-month prognosis.

Another question I am often asked is, “When is it the appropriate time to contact hospice?” People are sometimes taken aback by my most common response, which is often, simply, “today.” The reason I feel this is the most accurate answer is that by contacting hospice today, you have absolutely nothing to lose, but a priceless amount of information, support and services to gain. When contacted, many hospices will give you the option of having a nurse come to the home (or nursing home if that is where the patient resides) and explain the benefit. The nurse can
often tell you on the spot whether the hospice benefit may be available as an option now, or, if not, what criteria would need to be met in order to qualify.

Upon accessing the Hospice benefits, a registered nurse will be assigned whose focus will be on controlling the symptoms of the disease and helping to promote the best quality of life possible. The nurse will come to the home (usually from one to seven times per week, depending on need) for ongoing symptom management. There is also a registered nurse available 24 hours a day by phone for the hours that the assigned nurse is not available. A social worker will also be assigned who can assist in obtaining any available community resources, as well as helping
both the person with PSP and the family deal with the emotional aspects of the losses this disease can bring. A non-denominational pastor can also be assigned who can work alone or in conjunction with community clergy to help cope with the spiritual aspects of dealing with the disease.

In addition, nurse’s aides can be included to assist with personal care, such as bathing and dressing. Nurse’s aides generally visit from two- seven days a week, depending on need, and stay from 1-1 1/2 hours per visit. Trained volunteers can also become involved. They can help by making friendly visits to sit and read to the patient, running errands, assisting with rides to appointments or helping in any other way possible. Other services, such as speech or physical therapy, can also be included as part of the hospice plan of care. By invoking the benefit, you gain access to a team of welltrained professionals whose focus will be on providing the person with the absolute best quality of life possible. In addition to the professionals involved in the care, hospice also covers related medications as well as home medical equipment, such as walkers, wheelchairs, commodes, hospital beds and other equipment.

An additional positive aspect of the hospice benefit is that it can be provided not only in the home setting, but also in nursing facilities and hospitals. Often, people have other insurance in addition to Medicare, such as Medicaid or long-term care insurance. If this is the case, the additional insurance can sometimes be used to cover the cost of being in a nursing facility, while Medicare is used for the hospice services. Some patients choose to use hospice houses, which are facilities that
deal exclusively with hospice patients and often strive to create a more homelike environment as opposed to a medical one.

Of all the families I have had the pleasure and privilege of being involved with, the ones who have gained the most from the program all had one basic thing in common. They accepted all of the services and benefits hospice had to offer. Although there is no obligation to accept the involvement of all of the different team members, I strongly encourage doing so. Each member has something different to offer that often can compliment what the others provide.

Hospice is a benefit that is available much sooner than most people realize. Referrals for hospice evaluations can be made by patients, friends or family members, and can be called in directly to any hospice in your area. The service does not need to be initiated by a physician’s office, but it is often helpful to find out which hospices your doctor recommends.

William Carroll, RN, CHPN is a registered nurse who is nationally certified in Hospice and Palliative Care who is currently employed by HealthCare Dimensions Hospice, a subsidiary of The Dana Farber Cancer Institute.

[later on 12/22/09: removed a link Bill thought no longer appropriate.]

Using eye saccade velocity to distinguish PSP-P and PD

This interesting research out of Germany looked at 12 cases of the RS (Richardson’s Syndrome) form of PSP, 5 cases of the PSP-P (PSP-Parkinsonism) form, 27 cases of Parkinson’s Disease, and 23 healthy controls.  (It was just published on PubMed though the journal is dated Dec 2008 and the epub is dated 1/14/09.)

Cases of PSP-parkinsonism are characterized by asymmetric onset, tremor, and a moderate initial response to levodopa.  Obviously, PSP-P cases are frequently confused with Parkinson’s Disease.

Because PSP-P and PD are so similar in symptoms, clinicians need a way to differentiate the two disorders.  The German researchers conclude that video-oculography (VOG) can be used because of the “clear-cut separation between PSP-P and [PD] obtained by measuring saccade velocity.”  Typically, a neuro-ophthalmologist has the equipment to conduct a VOG.

It should be noted that none of the patients had pathologically-confirmed diagnoses, so the results may change based upon that.

Robin
———————————

Journal of Neurology. 2008 Dec;255(12):1916-1925. Epub 2009 Jan 14.

Differential diagnostic value of eye movement recording in PSP-parkinsonism, Richardson’s syndrome, and idiopathic Parkinson’s disease.

Pinkhardt EH, Jürgens R, Becker W, Valdarno F, Ludolph AC, Kassubek J.
Dept. of Neurology, University of Ulm, Ulm, Germany.

Vertical gaze palsy is a highly relevant clinical sign in parkinsonian syndromes. As the eponymous sign of progressive supranuclear palsy (PSP), it is one of the core features in the diagnosis of this disease.

Recent studies have suggested a further differentiation of PSP in Richardson’s syndrome (RS) and PSP-parkinsonism (PSPP).

The aim of this study was to search for oculomotor abnormalities in the PSP-P subset of a sample of PSP patients and to compare these findings with those of (i) RS patients, (ii) patients with idiopathic Parkinson’s disease (IPD), and (iii) a control group. Twelve cases of RS, 5 cases of PSP-P, and 27 cases of IPD were examined by use of video-oculography (VOG) and compared to 23 healthy normal controls.

Both groups of PSP patients (RS, PSP-P) had significantly slower saccades than either IPD patients or controls, whereas no differences in saccadic eye peak velocity were found between the two PSP groups or in the comparison of IPD with controls.

RS and PSP-P were also similar to each other with regard to smooth pursuit eye movements (SPEM), with both groups having significantly lower gain than controls (except for downward pursuit); however, SPEM gain exhibited no consistent difference between PSP and IPD.

A correlation between eye movement data and clinical data (Hoehn & Yahr scale or disease duration) could not be observed.

As PSP-P patients were still in an early stage of the disease when a differentiation from IPD is difficult on clinical grounds, the clear-cut separation between PSP-P and IPD obtained by measuring saccade velocity suggests that VOG could contribute to the early differentiation between these patient groups.

PubMed ID#: 19224319   (see pubmed.gov for this same abstract)

“Living with PSP: Norma’s Story”

I stumbled across this 6-minute video today:

“Living with PSP: Norma’s Story”
July 17, 2009
www.youtube.com/watch?v=6w-aL9_iQbI

It features Norma (with PSP), her husband Joe, and her daughter Susan.

The daughter’s advice:

  • communicate with the neurologist
  • find a local support group
  • lay the groundwork now for help and community resources

Norma’s advice:

  • be active

The husband’s advice:

  • take life as it comes, but with humor

Perhaps those dealing with a recent diagnosis of PSP would get something out of this video, or perhaps any PSP patient would value seeing that they are not alone.

I don’t know why but this video is titled “Physical therapy: Turn and sit” and is supposed to feature physical therapist Heather Cianci.  (It’s listed this way on the CurePSP website and on YouTube.)  “Norma’s Story” has nothing to do with PT.  I believe this video was posted to YouTube by CurePSP.

Robin

 

The “Other” Dementias (featuring Lewy Body Dementia story)

There’s a wonderful article in the November/December 2009 issue of Neurology Now magazine.  It features Jerome and Renata Rafferty; Jerome had Lewy Body Dementia and Renata was his caregiver.

Renata is a fixture on the LBDA Forum (“raffcons”).  (She and Jerome used to live near Palm Springs; they moved to Indiana this spring.)  Renata emailed me on Sunday about the article:

“The writer interviewed me just a  few days before Jerome died, and it was a fitting cap to bring at least some usefulness to what Jerome went through. I think the article is pretty good and would like to see it disseminated as widely as possible.”

Here’s the full text of the article, and a link to it online.  In the online version, you can see a nice photo of Jerome and, of course, the formatting is prettier.  You can also download the PDF of the article.

Robin

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journals.lww.com/neurologynow/Fulltext/2009/05060/The__Other__Dementias.14.aspx –> HTML version

The “Other” Dementias
Alzheimer’s disease is not the only cause of dementia. Knowing the others may help you or your loved one get the right diagnosis and treatment.
by Tom Valeo
Neurology Now:
November/December 2009 – Volume 5 – Issue 6 – p 26-27, 31-34

Renata Rafferty first suspected trouble when her late husband Jerome, a bright, curious, and articulate man, couldn’t tell her about an article he had just read.

“He would start to tell me and then say, ‘I’d better go find the article and give it to you’,” she recalls.

Jerome was nearly 70 at the time (he died on Oct. 20, 2009, at the age of 76), so Rafferty attributed such lapses to typical age-related forgetfulness. But that wasn’t the first disturbing change she had noticed in him. For more than two years he had been having terrifying dreams several nights a week.

“They were scary, violent dreams, and he would act them out,” Rafferty remembers. “He would kick, push, and speak angrily, and if I tried to wake him he’d lash out at me. I learned to get out of bed, shake his foot, and call to him so I wouldn’t be close enough to get hurt.” Their doctor attributed the dreams to the pain medication Jerome had been taking for a ruptured disc in his back. But he prescribed the Alzheimer’s drug donepezil when Jerome could no longer follow the plot of Law and Order, one of his favorite TV shows. A neurologist added another Alzheimer’s medication, memantine.

After Jerome went through eight hours of neuropsychiatric testing over two days, the doctor who administered the tests concluded he did not have Alzheimer’s disease (AD) but rather vascular dementia, which is caused by the damage that accumulates from several small strokes.

Since strokes can occur in any part of the brain, the symptoms of vascular dementia can vary greatly. But they often cause memory problems, mood disorders, and difficulty with walking and other movements-symptoms found in some Alzheimer’s patients as well.

If the strokes accumulate in the front of the brain, they may produce symptoms of frontotemporal dementia (FTD). This group of disorders affects the prefrontal cortex, which modulates mood, judgment, speech, creativity, and other distinctly human functions.

Still, the neuropsychologist who performed the testing insisted Jerome had vascular dementia, and predicted that unlike patients with AD, who decline steadily, Jerome would decline, remain stable for a while, then have another small stroke and decline again, and so on.

“We went for a year or so thinking it was AD, and then we went for another year or so thinking it was vascular dementia,” Rafferty says.

Then Jerome went to the Mayo Clinic in Scottsdale, AZ, seeking relief from his persistent back pain. After a thorough exam his doctors concluded that Jerome did not have vascular dementia or AD. They had noticed that the toes on one foot were constantly wiggling, a sign of a very rare condition known as painful leg moving toe syndrome.

“Everyone was very excited about that,” Rafferty says. “They wanted to enroll him in a study, videotape his foot and leg.”

But during the exam she heard the senior neurologist on the team mention–in passing–that Jerome did not have vascular dementia, so she followed him into the hall and asked him what he meant.

“I’m so sorry to tell you this, but it’s obviously Lewy body dementia,” he said, and rushed off.

“That was the first time I heard those words,” Renata says.

Now that she knows more about Lewy body dementia (LBD), she can see early symptoms that should have pointed to the diagnosis. Acting out violent dreams, for example, is one poorly understood symptom of the disorder. And when Jerome took olanzapine, one of the newer drugs used to treat psychiatric symptoms, he had a violent reaction that produced high blood pressure and delirium.

“It turns out that this is a sign of LBD too,” Rafferty says. “We found out that people with LBD often have a severe reaction to atypical antipsychotic medications-also, that LBD patients should not be put under general anesthesia because they may proceed rapidly to end-stage disease.”

To complicate the diagnosis further, LBD may overlap with other conditions, including AD, Parkinson’s disease, FTD, and vascular dementia. Although Jerome did not have vascular dementia, he did have a fourth transient ischemic attack-a temporary interruption of blood flow to a part of the brain. A brain scan revealed signs of a previous stroke, which could have produced symptoms of its own.

Despite his memory problems, and occasional hallucinations, and fleeing bouts with anxiety and aggression, Jerome remained acutely aware of his condition in a way that Alzheimer’s patients seldom are. When a hospice nurse recently asked him if he needed anything, he replied with a mordant, “Yeah, a getaway car.”

THE BIG FOUR

Everyone knows about AD, which accounts for 65 percent of all dementia in the United States. Alzheimer’s begins with degeneration of the hippocampus, a brain structure essential for the creation of new memories, and spreads to other brain areas, producing problems with speech, mood, judgment, motor skills, and other abilities.

But the hippocampus is not the only region subject to degeneration. Other brain structures can develop problems, and although they may produce similar symptoms, the underlying diseases each have a life of their own.

“There are well over 100 causes of dementia, but the big four that make up 94 to 98 percent are Alzheimer’s disease, Lewy body dementia, frontotemporal dementia, and vascular dementia,” notes James E. Galvin, M.D. M.P.H., assistant professor of neurology, anatomy, and neurobiology at Washington University School of Medicine and director of the Memory Diagnostic Center and the Wolff Neuroscience Laboratory. If you take 100 people with dementia, 65 will have AD, 10 or 12 will have LBD, 10 or 12 will have vascular, and eight will have FTD.

Because Alzheimer’s was identified more than 100 years ago and accounts for the vast majority of dementia, it attracts the largest number of research dollars, and therefore is better understood than the others.

But the other types of dementia tend to strike earlier, consuming many years of productive life.

“These other diseases affect people in their 50s, 60s, and early 70s,” observes Dr. Galvin. “Alzheimer’s affects people in their late 70s and early 80s.”

Although the precise causes of these different dementias (including AD) remain obscure, they all seem to involve the faulty production or management of proteins in the brain. In AD, tau protein accumulates within the body of neurons, while amyloid protein forms clumps in between neurons.

In LBD, a protein known as alpha-synuclein aggregates into clumps named after Frederich Lewy, the German-American physician who described them in 1912. (Dr. Lewy worked in the same lab as Dr. Alois Alzheimer, who identified the protein clumps and tangles characteristic of the disease named after him.)

FTD involves the accumulation of a protein known as TDP-43, which also plays a role in amyotrophic lateral sclerosis (ALS), or Lou Gehrig’s disease. Discovered just three years ago, TDP-43 plays such a decisive role in both diseases that some researchers suspect that FTD and ALS may be different manifestations of the same disease process.

One type of FTD known as Pick’s disease, named after Arnold Pick, a professor of psychiatry at the University of Prague who described the disease in 1892, involves the accumulation of tau protein-one of the two proteins associated with Alzheimer’s disease. In Pick’s disease, however, the protein accumulates in the frontal lobes, where it causes erratic behavior and the loss of normal inhibitions. A normally reserved man with Pick’s might make lewd sexual comments to women or become belligerent. Pick’s disease may also produce speech difficulties that eventually leave the patient mute.

Vascular dementia is an imprecise term that refers to dementia caused by brain cells that have been damaged by lack of oxygen from several small strokes. Some research suggests that the most common form of vascular dementia, known as multi-infarct dementia, merely causes or accelerates AD, producing a decline in memory and cognitive function.

“There can be some overlap in pathology, but in vascular dementia you think the primary dementing component is due to vascular disease,” says Dr. Galvin. “If you have AD and then have a stroke, you don’t then have vascular dementia too; you have AD and a stroke. It’s not clear cut, though.”

WHAT IS DEMENTIA?

Understanding dementia, which is a complex and varied dysfunction, requires understanding the complex and varied function of the brain itself.

What we experience as consciousness involves the seamless integration of signals generated by dispersed regions of the brain. To produce accurate perceptions of the environment, appropriate emotions, reliable memories, and good judgment, brain regions must perform efficiently, and the fibers that link those regions must transmit signals smoothly and swiftly.

All this activity depends on the ability of brain cells, known as neurons, to manufacture, transport, and recycle proteins, a process that requires huge amounts of glucose and oxygen. (The brain accounts for two percent of the body’s weight, but consumes 20 percent of the body’s energy.)

This constant and arduous process provides many opportunities for mistakes. A neuron may start to manufacture defective or misfolded proteins, or fail to manufacture enough to provide the chemical signals that enable neurons to communicate with each other. Proteins may not be broken down or recycled efficiently enough, causing debris to build up within and between the neurons, which can result in harmful inflammation.

This variety of brain functions points to one of the great mysteries of dementia: Why do various regions of the brain degenerate so differently?

“It’s what we call selective vulnerability, and no one understands why it exists,” says Bradley Boeve, M.D., professor of neurology at Mayo Clinic College of Medicine in Rochester, MN. “Why does AD affect the hippocampus, while FTD affects the frontal and temporal lobes and LBD affects the brainstem and neurochemical centers? I’ve never heard a good hypothesis as to why. Even in patients with end-stage FTD, their parietal and occipital regions [other major brain regions] look pretty normal. If dementia is a protein dysfunction, why is it so selective for certain parts of the brain?”

The variety of dementia makes treatment extremely difficult. Antipsychotic drugs, for example, quell the voices and hallucinations of schizophrenia and help some people with AD, but often produce delirium in LBD patients.

And the complexity of the brain-from protein synthesis within the neuron to the dense highways that transmit signals-makes effective treatments difficult to devise, leaving physicians with little to offer but relief for some symptoms. Donepezil, for example, developed to stimulate the memory of AD patients, may help people suffering from another form of dementia that causes memory problems. Patients with LBD who develop rigidity of movement may benefit from drugs used to treat Parkinson’s disease. Such drugs do nothing to treat the underlying cause of the dementia but may provide some relief from the consequences.

WHAT GOES WRONG?

The investigation of Alzheimer’s disease demonstrates how elusive the cause of dementia can be. For nearly a century scientists believed that AD was caused by the plaques and tangles that Alois Alzheimer spotted through his microscope in the brain tissue of a women who had been severely demented. (The tissue had been taken at autopsy.) Inside of the neurons he found neurofibrillary tangles-strands of tau protein that looked like a length of thread crammed into a ball. Between the neurons he found clumps of amyloid protein, which he dubbed amyloid plaques.

The solution seemed obvious: Get rid of the plaques and tangles. But treatments that clear the brain of these toxic proteins have failed to cure the disease, suggesting that tangles and plaques develop relatively late in the disease process.

The same may be true of other dementias. The toxic proteins they produce probably are not the cause of the problem but the consequence, and an understanding of the cause may be many years away.

In the meantime, is there anything we can do to reduce the risk of dementia?

“Pick your parents well,” says Dr. Galvin, noting that genes seem to predispose some people to dementia. In addition, exercise that promotes cardiovascular health will help deliver a generous supply of blood to the brain, providing neurons with the nutrients they need. Keeping the brain active also helps, according to Dr. Galvin.

“But that’s not absolute,” he adds. “There are astrophysicists who are also vegetarian marathoners who get dementia, and couch potatoes who don’t. But from a population perspective, those behaviors seem to afford some protection.”

Other advice: If someone diagnosed with AD doesn’t appear to have the right symptoms, voice skepticism.

“If you suspect that it’s not AD but one of these other dementias, see a neurologist, preferably a cognitive neurologist well versed in these disorders,” says Dr. Boeve. “A lot of primary care physicians haven’t been as well educated in these less common disorders, so they may not recognize them. I hear this from families all the time: My doctor diagnosed AD, but I read about AD and it doesn’t sound like AD. And they’re usually right.”

That’s why Renata Rafferty spoke to Neurology Now about her husband’s long and arduous illness: to encourage others to be skeptical of a diagnosis of Alzheimer’s disease when the symptoms don’t seem right, and to educate themselves about other dementias that the doctor may not be considering.

“I have made it my personal mission to talk to people about Lewy body dementia, she says. I have my little elevator speech ready in which I describe symptoms that are not typical of Alzheimer’s, and I don’t hesitate to suggest that people with those symptoms be evaluated for one of the other dementias.”

“The Big Four” dementias – AD, LBD, FTD, and Vascular

There’s a wonderful article in the November/December 2009 issue of Neurology Now magazine.  It features Jerome and Renata Rafferty; Jerome had Lewy Body Dementia and Renata was his caregiver.

The “Other” Dementias (featuring Lewy Body Dementia story)

A companion article is titled “The Big Four.”  It gives short descriptions of four types of dementia – Alzheimer’s, Lewy Body Dementia, Frontotemporal Dementia, and Vascular Dementia.  The article notes that there are over 100 types of dementia.

Below the full text of the article, and a link to it online. You can also download the PDF of the article.

Robin
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journals.lww.com/neurologynow/Fulltext/2009/05060/The__Other__Dementias.14.aspx –> HTML version

The Big Four
Neurology Now
November/December 2009 – Volume 5 – Issue 6 – p 26-27,31-34

More than 100 types of dementia have been found, but four of them account for nearly 98 percent of all cases of dementia in the United States.

ALZHEIMER’S DISEASE (AD)

DESCRIPTION: People with AD develop memory problems, often followed by confusion, apathy, depression, emotional volatility, and other problems.

CAUSE: People with AD develop two types of dysfunctional protein in the hippocampus, the part of the brain essential for creating new memories. Tau protein accumulates within neurons in that region, while clumps of amyloid protein develop between neurons in that region. Some researchers, however, suspect that the toxic proteins may be the result of the disease rather than the cause.

TYPICAL CASE: The first symptom of AD almost always involves memory problems, such as forgetting familiar names and misplacing items. As the disease progresses people may have trouble finding their way home or keeping up with routine obligations such as doctor appointments, paying bills, and preparing meals. Later stages may affect the frontal lobes, resulting in erratic emotions, loss of normal inhibition, and hallucinations.

TREATMENT: Since AD results in decreased levels of acetylcholine, a neurotransmitter essential for memory and learning, drugs that boost acetylcholine, such as donepezil and memantine, often help, at least for a while. Other treatments are available for specific symptoms such as depression, hallucinations, and movement disorders, but nothing seems to slow development of the disease.

ON THE HORIZON: Several drugs and vaccines designed to inhibit the production of toxic tau and amyloid protein, or remove it once it appears, are in development. However, people who have tried the drug experimentally failed to improve significantly, even though protein levels declined, sometimes dramatically.

LEWY BODY DEMENTIA (LBD)

DESCRIPTION: Like Alzheimer’s, LBD produces cognitive decline, but with three additional traits. Instead of declining continuously, people with LBD tend to fluctuate in terms of attention, alertness, ability to speak coherently, and other symptoms. They also tend to have visual hallucinations, often benign. Finally, they tend to develop symptoms of Parkinson’s disease, including rigidity, tremor, and slowness of movement.

CAUSE: A type of protein known as alpha-synuclein clumps into Lewy bodies, which appear inside of cells, or neurons. Lewy bodies may result from the inability of the cell to break down and recycle alpha-synuclein efficiently. As the protein accumulates, it sticks together, as though the cell is trying to gather its own debris to keep it out of the way.

TYPICAL CASE: People with LBD often act out violent dreams that involve being pursued or attacked. They may develop benign hallucinations involving, for example, children or animals running around the house. Attention and concentration may fluctuate, and patients may start to have trouble with visual-spatial abilities-they may misjudge the height of a step or miss a cup when they reach for it. Some people with LBD experience an overwhelming urge to sleep during the day. Their movements also may become rigid and slow, like the symptoms of Parkinson’s disease, and they may develop problems with memory, judgment, and mood, like the symptoms of AD.

TREATMENT: No treatment specifically for LBD exists. However, since LBD affects nearly every neurochemical system in the brain, specific aspects of the disease can be treated. Memory problems can be treated with donepezil and other drugs for AD. Movement disorders may respond to L-dopa and other medications for Parkinson’s disease. Modafinil may alleviate daytime sleepiness.

ON THE HORIZON: No drug yet exists that affects the synuclein protein, although some drugs exist for daytime sleepiness, and another, which resembles methylfenidate, is in development.

FRONTOTEMPORAL DEMENTIA (FTD)

DESCRIPTION: FTD includes several disorders that cause the frontal lobes behind the forehead, and the temporal lobes at the sides of the brain, to atrophy and shrink. Patients either develop speech difficulties, known as aphasia, or they display inappropriate social behavior. Aphasia may involve halting, effortful speech with the patient struggling to produce the right word. Behavioral changes may involve indifference to the concerns of others. Some patients developing FTD may start shoplifting or become attracted to shiny objects or fire.

CAUSE: In FTD, a protein known as TDP-43 accumulates within cells at the front of the brain. In one form of FTD known as Pick’s disease, tau protein, found in the hippocampus of people with AD, accumulates within cells in the frontal lobes.

TYPICAL CASE: A person developing FTD generally exhibits personality or mood changes. An outgoing person may become withdrawn and depressed, while an introverted person may become loud and outgoing. Socially inappropriate behavior may also become more common. Later, FTD patients may develop speech difficulties as they lose the ability to recall the meaning of words, or they may start to speak with great fluency while making no sense.

TREATMENT: Only symptomatic treatments are available with medications developed for other disorders, such as psychiatric medications for behavioral problems or mood disorders. There are no treatments for language problems.

ON THE HORIZON: Methylene blue, a drug in development for AD, inhibits the aggregation of tau protein, so it may help patients with Pick’s disease. Another tau aggregation inhibitor known as AL-108, or davunetide, is in clinical trials, and may soon become the first tau-active drug available in the U.S. TDP-43, the offending protein in other forms of FTD, was discovered only three years ago, leaving little time for the development of effective treatments.

VASCULAR DEMENTIA

DESCRIPTION: Since this dementia results from several small strokes, and strokes can affect any part of the brain, the symptoms of vascular can vary widely. However, they usually include declines in problem-solving ability, memory, and socially appropriate behavior.

CAUSE: Vascular dementia is believed to result from damage to brain cells caused by lack of oxygen when the blood supply is cut during a series of mild strokes. However, one study of 1,000 brains from demented patients who had died found only six that had pure vascular dementia, with the slow progression typical of the disorder. The rest also had another form of dementia.

TYPICAL CASE: To be diagnosed with vascular dementia, a patient must show evidence of a stroke in a location that could affect cognition, and cognitive problems must develop within three to six months of the stroke. A patient who meets these criteria may develop memory problems and have trouble speaking coherently or understanding the speech of others. They may also develop motor difficulties that prevent them from dressing themselves.

TREATMENT: The first goal is to reduce stroke risk by improving cardiovascular health. Statins may be prescribed to lower cholesterol, anti-hypertensives to lower blood pressure, and omega-3 pills to improve triglyceride levels. Low-dose aspirin may be prescribed to inhibit the clotting of the blood, and patients may be urged to give up smoking and drinking and reduce stress.

ON THE HORIZON: Damage from strokes cannot be reversed, but the brain can compensate for some deficits. Physical therapy designed to stimulate brain plasticity may provide some help.

Copyright © 2009, AAN Enterprises, Inc.

Famous amnesic launches a bold, new brain project at UCSD’s Brain Observatory

This post is likely only of interest to those curious about brain tissue analysis. I’ve been watching the slicing of this brain tissue today at UCSD’s Brain Observatory, and agree that it’s “mesmerizing.” The process will produce about 2500 tissue samples for analysis.

Here’s the live video:
http://thebrainobservatory.ucsd.edu/hm_live.php

In the New York Times article from yesterday on this “famous brain” — http://www.nytimes.com/2009/12/03/healt … brain.html — a researcher said “It’s just amazing that this one patient — this one person — would contribute so much historically to the early study of memory.”

And here’s a good article on the Brain Observatory and the analysis of this particular brain from Monday’s San Diego Union-Tribune newspaper. For me, the last two sections of the article were the most interesting (starting with “The Brain Observatory is divided between…”).

http://www3.signonsandiego.com/news/200 … ld-new-br/

H.M. recollected
Famous amnesic launches a bold, new brain project at UCSD

By Scott LaFee, San Diego Union-Tribune Staff Writer
Monday, November 30, 2009 at 12:04 a.m.

As best he could remember, Henry Gustav Molaison never visited San Diego, spending his entire life on the East Coast. When he died late last year at the age of 82, Molaison was a man almost entirely unknown except by his initials H.M. and the fact that experimental brain surgery had erased his ability to form new memories.

He forgot names, places, events and faces almost immediately. Half an hour after lunch, he couldn’t recall what he had eaten, or that he had eaten at all. His face in the mirror was a constant surprise because he remembered only what he looked like as a young man. Every question was new, even those asked just minutes before.

Yet Molaison bore this strange and unimaginable burden with grace and stoicism, allowing scores of scientists to study, probe and ponder his condition for decades, each seeking to better understand the mysteries of the human brain, memory and personal identity.

“H.M. started a revolution in the study of memory,” said Dr. Vilayanur S. Ramachandran, a professor of psychology and neuroscience and director of the Center for Brain and Cognition at UCSD at the time of Molaison’s death. “His was an unforgettable contribution.”

Molaison died of respiratory failure on Dec. 2, 2008, but his story — and his legacy — does not end in that Connecticut nursing home. Within hours of death, Molaison’s brain would be scanned, removed and placed in the preservative formalin, the first steps on a journey to San Diego and a new kind of immortality.

On a cold night in mid-February, Jacopo Annese returned to San Diego, arriving on Jet Blue Flight 411 from Boston. With him was the brain of H.M. They had flown coach: Annese in the aisle seat, H.M.’s brain in a 19-quart white plastic cooler strapped next to him in the window seat. More than a few fellow travelers looked curiously at the arrangement; some inquired directly.

“I tried not to be coy,” said Annese. “I told them the cooler contained a very important scientific specimen. I didn’t say a brain. I didn’t want to risk upsetting any passengers.”

Sophisticated and articulate, educated and trained in Italy, England and the United States, the 43-year-old Annese came to the University of California San Diego in 2005 to develop and direct the Brain Observatory, with an ambitious plan to create a new and unrivaled collection of human brains for scientific study.

These brains, normal and with various pathologies, will be preserved on thousands of slides that, in turn, are converted into extraordinarily high-resolution digital images freely available online. Researchers around the world will be able to use the material to conduct investigations ranging from parsing basic cognitive functions or the physical effects of diseases like Alzheimer’s to more abstract inquiries such as how memories are created and changed and the organic nature of consciousness.

The project has already begun with a handful of brains. Annese envisions the collection as a kind of library, each brain containing a life story. “We strive to treat the brains we study not as anonymous tissue, but as representations of a person and of a mind. We want to write books about people’s lives, neurological biographies that survive in glass and pixels.”

In this most novel of libraries, Molaison’s brain is the rarest of volumes. He is the most famous amnesic of all time, perhaps the most-studied neurological patient in history.

When he was 10 years old, Molaison began suffering epileptic seizures and blackouts, which increased in severity and frequency until, in his 20s, he was no longer able to work or live alone. In 1953 at the age of 27, Molaison agreed to undergo a radical experimental operation intended to relieve his suffering. Dr. William Beecher Scoville, a noted neurosurgeon at Hartford Hospital in Connecticut who had refined many of the techniques used in lobotomies, suctioned out finger-sized portions of the temporal lobes on both sides of his brain. The removed tissue contained most of Molaison’s hippocampus, a brain region whose function was poorly understood at the time, if at all.

The seizures largely stopped, but so too did Molaison’s ability to form new memories, though he could recall parts of his life before the surgery, a condition called severe anterograde amnesia. Scoville and a Canadian psychologist named Brenda Milner quickly realized that Molaison represented a tragic but rare opportunity to explore how human memory works.

With Molaison serving as willing and genial subject, identified only as H.M. to protect his privacy, they began a series of studies. In a landmark 1957 paper, Scoville and Milner described H.M.’s bifurcated memory for the first time. The paper, which has been cited by other researchers almost 2,000 times, led to the startling realization that memory is not a generalized brain function, but rather is controlled by key regions like the hippocampus, which regulates the flow of information destined to become long-term memory.

In many ways, H.M. appeared to be an ordinary fellow. He liked crossword puzzles and watching TV. He was polite, funny and self-effacing. “He was a very endearing person,” said Annese, who met H.M. once in 2006 during early planning for the Brain Observatory and library. “I was happy to get to know the man.”

Surprisingly, even with no ability to form long-term memories, H.M. could learn new things, in particular new muscle memory skills like drawing or playing golf. He didn’t remember taking lessons or practicing, but the acquired abilities stuck.

That discovery generated another new and fundamental insight into human cognitive function. There are different types of memories: Long-term declarative memories, which H.M. could no longer form; short-term memories which H.M. still possessed to a degree; and motor memories, such as recalling how to ride a bike, which H.M. never lost.

Each kind of memory, scientists deduced, must essentially be created and reside in different parts of the brain. Sometimes H.M. learned and remembered things that happened post-surgery, such as the assassination of John F. Kennedy in 1963. This suggested portions of H.M.’s memory system survived his 1953 surgery or that other regions had taken up some of those duties. No one really knew.

To really understand what was going on inside H.M.’s head, researchers needed to venture more deeply inside the brain itself.

The Brain Observatory is divided between an elaborately equipped wet lab for handling flesh-and-blood brains, and separate areas housing high-powered microscopes and computers for digitizing them.

Converting biology to bytes takes time. It is complex, painstaking and fraught with unprecedented technical challenges. A brain like H.M.’s represents a singular chance to advance scientific knowledge, but there is almost no room for mistakes.

“It’s a huge responsibility that many labs might not want,” said Annese.

Within four hours of his death, Molaison’s body was moved to Massachusetts General Hospital (MGH), where researchers, led by Suzanne Corkin, a professor of behavioral neuroscience at the Massachusetts Institute of Technology who had worked with H.M. for 46 years, conducted an overnight series of magnetic resonance imaging scans, a last chance to record his brain’s structure and condition “in situ.”

The next morning, after Annese had flown overnight to get there, he and MGH neuropathologist Matthew Frosch delicately removed H.M.’s brain from his skull.

“I was sweating bullets,” Annese later told the journal Science.

Like all fresh brains, H.M.’s had the consistency of Jell-O. It could be easily damaged, harm that might render it less useful — perhaps even useless — for further study. But the removal went smoothly and the brain was immediately deposited in formalin, suspended by a string so that it wouldn’t become deformed by resting on the bottom of the container. It would remain in formalin for two months until firm enough to travel safely to San Diego.

After returning in February with the brain, Annese conducted a second, more exhaustive series of MRI scans over two days, producing a more comprehensive anatomical map and a final record of the brain intact.

Next, the brain was immersed for weeks in increasing levels of sucrose solution. As the sucrose (sugar) infused the brain, it replaced water in cells, reducing the risk that ice crystals might later form, which could cause tissue to tear and reduce the brain’s research value.

High-security freezers house the project’s brains. (Annese has 10 so far.) The freezers are constantly and continuously monitored, with emergency backup power and an automatic alert system.

H.M.’s brain is scheduled to be sectioned on Wednesday, with segments of the procedure broadcast live via the Brain Observatory’s Web site (thebrainobservatory.ucsd.edu). Annese has been practicing the procedure on control brains.

Just prior to cutting, H.M.’s brain will be dipped in a liquid bath of isopentane at minus 40 degrees Celsius until frozen solid. The actual slicing is reminiscent of a delicatessen. The prepared brain is locked inside a cuff containing circulating ethanol to keep it precisely frozen. Too cold and the tissue might shatter during cutting; too warm and the tissue becomes sloppy. The cuff and brain are then mounted atop a commercial microtome modified by Annese with help from machinists at the Scripps Institution of Oceanography. Every component has been meticulously measured and engineered. A razor-sharp blade of tempered steel glides over the exposed brain, cutting from the front of the brain to the back, producing opaque, whitish slices that crinkle and wad on the blade’s edge like slivers of cut ginger.

Each brain slice is approximately 70 microns thick, about the width of a hair. An average-sized brain produces 2,600 to 3,000 such slices. Once the cutting begins, it continues until the brain is completely sectioned, a 30-hour endeavor.

A camera mounted above methodically records every slice, though a human operator must constantly attend to gently dab up each crumpled slice off the blade and deposit it into a sequentially numbered container filled with buffer solution.

“There’s something mesmerizing about doing this,” said Natalie Schenker, a postdoctoral research associate as she dabbed and deposited slices of control brain. “It’s like going on a journey, each slice getting you to another place in the brain.”

The majority of slices will be left untouched, cryogenically preserved for future experiments. Some slices, perhaps every 30th to 50th, will be mounted on postcard-sized glass slides. Mounting is an exacting process. A technician uses fine arts brushes to tease a wadded slice floating in a tray of buffer solution to lie flat upon an underlying slide, a physical match to the photo taken of that same slice during the cutting procedure. One mounting can take up to an hour.

The slides are then dried and some sequentially stained, what Annese calls “the club sandwich idea.” Different stain colors reveal different components of the brain. Blue shows individual neurons; brown highlights myelin-coated connective structures and support cells.

Finally, the slides are ready to be digitized. Each is placed under a microscope at 20X magnification to distinguish individual cell types. A computerized camera next begins snapping pictures of the microscopic scene. It requires 20,000 such “capture tiles” to produce a mosaic of just one slide, enough digital information to fill 200 DVDs.

Annese and colleagues have designed an automated system to do this demanding but tedious work. The data are sent to UCSD’s California Institute for Telecommunications and Information Technology (Calit2) and the San Diego Supercomputer Center, where it will be managed and stored for future use.

A fully sliced, mounted, stained and digitized brain is, in some ways, a return to wholeness, a brain reassembled in cyberspace. “We’re taking all of the two-dimensional image data (from the slides) and reconstructing them in a 3-D system,” said Alain Pitiot, a computer scientist at the University of Nottingham in England. “We’re reforming the brain so that researchers can see things in context.”

The intended result will be a bit like Google Earth. Scientists will be able to zoom in and out of a digitized brain; focusing down to the level of individual neurons or pulling back to examine whole brain circuits or regions.

When fully up and operating, the project will be an interactive affair. All data will be online and open to viewing and discussion. Neuroscientists will be able to watch procedures, make recommendations and observations, suggest experiments or request tissue samples. Nonscientists will have similar, if more limited, access.

For obvious reasons, H.M.’s brain holds special interest. It’s the catalyst for the entire endeavor. But more importantly, researchers are eager to compare what they learned about Molaison while he was alive with what they can discover in his digitally revealed brain.

“The extraordinary value of H.M.’s brain is that we have roughly 50 years of behavioral data, including measures of different kinds of memory as well as other cognitive functions and even sensory and motor functions,” said Corkin at MIT.

“We know what he was able to do and not do. Our goal is to link his deficits to damaged brain areas and his preserved functions to spared areas.”

H.M.’s brain will also be compared with those of other amnesic patients. Larry Squire, a professor of psychiatry and neurosciences at UCSD, has donated the brains of three much-studied patients. Some of Ramachandran’s patients have also agreed to donate their brains after death.

But the Brain Observatory and library project is about more that just H.M. and the mystery of memory. It promises the chance to investigate all things that ail the brain. For example, Annese is already processing brains that are part of an HIV study. And he has established partnerships with Lifesharing and the San Diego Eye Bank, which handle organ and tissue donations in San Diego County, to secure new donors.

Annese is quick to note that he’s not solely interested in afflicted or particular brains. He hopes people who have no known neurological issues will donate their brains to the Observatory, too.

“Healthy brains for study are very rare, but they are essential if we want to understand how brains age and why some people avoid neurological disease and dysfunction. We want to know what a normal brain is.”

But more profoundly, Annese hopes the Observatory and the future research that flows through and out of it will help answer the enduring question of what exactly makes each of us human and unique.

“We know that the human brain has a basic pattern,” said Annese. “We’re all born with the same kind of instrument, let’s say a violin. But how we play this violin and what we decide to play shapes this instrument during our lives. We can learn a lot by the wear-and-tear of life on our violins, how each of us has modified it. These could prove to be anatomical fingerprints of individuality, biological clues of what makes us who we are.”

OBSERVING LIVING DONORS IS PART OF STUDY

The Brain Observatory and its related brain library project will necessarily rely upon donated brains, primarily through the services of two regional organ and tissue banks, Lifesharing and the San Diego Eye Bank.

Much of the emphasis will be on finding donors who are able to participate in a monitoring, data-gathering program while they are still alive and well, people like Clint and Maggie Spangler.

The La Jolla couple is reasonably healthy. “I’m told I have the brain of a 60-year-old,” said Clint, who is 81. Nonetheless, he and his wife both suffer from essential tremor, a progressive neurological condition characterized by uncontrollable trembling, typically of the hands though it can affect many parts of the body.

Often confused with Parkinson’s disease, essential tremor is not life-threatening. “It’s more of a nuisance,” said Maggie. But it is common. According to the National Institutes of Health, the condition affects up to 14 percent of Americans over the age of 65.

The exact cause of essential tremor is not known, but there’s a clear genetic component. Two of the Spangler’s four children have the condition; a third appears likely to develop it. Clint and Maggie have promised their brains to the observatory, hoping that the donations might help researchers solve their condition and others.

“We’re not too philosophical about it,” said Maggie. “We’d like to be able to help, and we’re certainly not going to need our brains after we’re dead. Besides, do you know what a funeral costs these days?”

To learn more about organ and tissue donations, visit Lifesharing at lifesharing.org or the San Diego Eye Bank at sdeb.org

Correlations between language problems and brain pathology

This is an interesting French study correlating clinical symptoms related to language and speech with the pathology seen in autopsied brain tissue. Eighteen patients were monitored over a 15-year period. Four patients developed right-predominant corticobasal syndrome. One patient was given a clinical diagnosis of PSP.

“Of the 18 cases, 8 had FTLD-TDP, 3 had AD, 2 had PSP, 2 had CBD, 2 had PiD, and 1 had AGD,” upon brain autopsy. Of the two who had confirmed PSP diagnoses, one was diagnosed with the behavioral variant of FTD during life though the diagnosis was later changed to PSP when supranuclear palsy appeared. The other was diagnosed with corticobasal syndrome during life.

Of the four patients diagnosed with corticobasal syndrome during life, one had PSP upon brain autopsy, one had CBD, one had Pick’s Disease, and one had FTLD-TDP.

Of the two cases who had confirmed CBD diagnoses, one was diagnosed with FTDbv during life and the other with CBS during life.

The five patients who stopped speaking (“progressive anarthria”) all had tau pathology — either PSP, CBD, or Pick disease. (“[All] progressed to mutism, swallowing difficulties, and orofacial apraxia.”)

Findings of atrophy (on a CT or MRI) and findings of hypometabolism (on a SPECT) in nearly all of the the cases are provided along with info such as disease duration, MMSE score, Frontotemporal Behavior Scale rating, and Dementia Rating Scale score.

Eighteen patients is a very small study. We’ll have to see if the results can be replicated.

Robin

———–

Neurology. 2009 Nov 25. [Epub ahead of print]

Prediction of pathology in primary progressive language and speech disorders.

Deramecourt V, Lebert F, Debachy B, Mackowiak-Cordoliani MA, Bombois S, Kerdraon O, Buée L, Maurage CA, Pasquier F.
From the Memory Clinic (V.D., F.L., B.D., M.A.M.-C., S.B., F.P.) and Department of Neuropathology (O.K., C.-A.M.), CHU-Lille, Lille; University Lille Nord de France (V.D., F.L., B.D., M.A.M.-C., S.B., O.K., L.B., C.-A.M., F.P.), Lille; and INSERM (O.K., L.B., C.-A.M.), JP Aubert Research Centre, Lille, France.

OBJECTIVE: Frontotemporal lobar degeneration (FTLD) encompasses a variety of clinicopathologic entities. The antemortem prediction of the underlying pathologic lesions is reputed to be difficult.

This study sought to characterize correlations between 1) the different clinical variants of primary progressive language and speech disorders and 2) the pathologic diagnosis.

METHODS: The latter was available for 18 patients having been prospectively monitored in the Lille Memory Clinic (France) between 1993 and 2008.

RESULTS: The patients were diagnosed with progressive anarthria (n = 5), agrammatic progressive aphasia (n = 6), logopenic progressive aphasia (n = 1), progressive jargon aphasia (n = 2), typical semantic dementia (n = 2), and atypical semantic dementia (n = 2).

All patients with progressive anarthria had a tau pathology at postmortem evaluation: progressive supranuclear palsy (n = 2), Pick disease (n = 2), and corticobasal degeneration (n = 1).

All patients with agrammatic primary progressive aphasia had TDP-43-positive FTLD (FTLD-TDP).

The patients with logopenic progressive aphasia and progressive jargon aphasia had Alzheimer disease.

Both cases of typical semantic dementia had FTLD-TDP.

The patients with atypical semantic dementia had tau pathologies: argyrophilic grain disease and corticobasal degeneration.

CONCLUSIONS: The different anatomic distribution of the pathologic lesions could explain these results: opercular and subcortical regions in tau pathologies with progressive anarthria, the left frontotemporal cortex in TDP-43-positive frontotemporal lobar degeneration (FTLD-TDP) with agrammatic progressive aphasia, the bilateral lateral and anterior temporal cortex in FTLD-TDP or argyrophilic grain disease with semantic dementia, and the left parietotemporal cortex in Alzheimer disease with logopenic progressive aphasia or jargon aphasia. These correlations have to be confirmed in larger series.

PubMed ID#: 19940270 (see pubmed.gov for abstract only)

Robin’s note: I suggest looking up terms in wikipedia.