Special SPECT to diagnose CBD, PSP, and PD (French research)

PSP and CBD folks –

SPECT functional imaging is not widely available in the US. I think it is available in only a handful of medical research facilities. This was addressed in a Q&A* in May ’08 during a Parkinson Disease Foundation conference.

Some recently-published French research looks at the results of SPECT scans in 62 people with clinical diagnoses of CBD, PSP, and PD. The researchers were using a special kind of SPECT, called an HmPaO-SPECT, to differentiate between these three disorders. The researchers concluded that this type of SPECT scan can distinguish between these three disorders, quite accurately. “The frontal medial, temporoparietal and parietal regions were the most discriminant.”

The abstract follows. I won’t be getting this full article because it’s in French!

Robin

Revue Neurologique (Paris). 2009 Jan 14. [Epub ahead of print] [Classification of parkinsonian syndromes via factorial discriminant analysis of brain SPECT data.] [Article in French]

Kreisler A, Defebvre L, Duhamel A, Lecouffe P, Dujardin K, Steinling M, Pasquier F, Destée A.
Service de neurologie et pathologie du mouvement, hôpital Roger Salengro, Lille, France.

INTRODUCTION: The objective was to assess the value of single photon emission computerized tomography (SPECT) and factorial discriminant analysis (FDA) in the differential diagnosis of Parkinson’s disease (PD), progressive supranuclear palsy (PSP), and corticobasal degeneration (CBD).

PATIENTS AND METHODS: Sixty-two patients with clinical diagnoses of either CBD, PSP or PD were studied using brain HmPaO-SPECT. Thirteen pairs of regions of interest (ROIs) were drawn on the slices located 50mm and 90mm above the canthomeatal plane. Twenty-six uptake indices and 13 asymmetry indices were determined. FDA was performed in order to determine whether or not the patients could be classified into the correct clinical group on the basis of SPECT data alone. The most discriminant parameters were used to generate two predictive scores, which were tested in a second group of 15 patients.

RESULTS: FDA of all 39 variables correctly classified all the patients. A subset of 10 variables was used to build predictive scores, which correctly classified 90% of PD patients, 100% of PSP patients and 86% of CBD patients. When tested in the validation group of 15 patients, these predictive scores correctly classified 87% of the individuals. The frontal medial, temporoparietal and parietal regions were the most discriminant.

CONCLUSION: Using SPECT data alone, this study enabled us to distinguish between PD, PSP and CBD in patients with clear clinical presentations of the diseases in question. This novel, statistical approach provides reliable information. However, a prospective study dealing with de novo parkinsonian syndromes will be necessary.

PubMed ID#: 19150099 (see pubmed.gov)

* Question: Why are SPECT scans not available in the US?
Answer: Because of corporate changes. GE bought Amersham. Amersham wanted to bring another type of SPECT agent to market. It’s been found that the drug that GE started to bring to market in Europe is easier to use. So it got slowed down bringing this agent to the US. GE is talking to the FDA about using European trial data.

Brain Disorder Suggests Common Mechanism May Underlie Many Neurodegenerative Diseases

This news article from today is about Mayo Jax-led research. Eight families were studied worldwide. Multiple family members donating brain tissue made such research possible.

These eight families have a genetic defect “that results in profound depression and parkinsonism in a disorder known as Perry syndrome.” The clinical features of Perry syndrome “include early-onset parkinsonism (stiffness, slowness and rigidity), depression, severe weight loss, and increasing difficulty in breathing. Once symptoms occur, typically in the patient’s mid-40s, the disease is rapidly progressive and fatal.”

PSP is specifically mentioned. It seems from these two excerpts that these findings may relate to many other disorders:

“Although [Perry] syndrome is exceedingly rare, the mechanism implicated in it may help explain the origins of a variety of neurodegenerative disorders, such as Parkinson’s and amyotrophic lateral sclerosis diseases, and even common depression and sleep disorders that are also hallmarks of the disorder, the researchers say.”

“The findings may also shed light on other neurodegenerative disorders, the researchers say. In Alzheimer’s disease, frontotemporal dementia and progressive supranuclear palsy, for instance, the ‘spikes,’ comprised of microtubule associated protein tau (MAPT), that normally stabilize and secure these rails tend to fall apart.”

Here’s the full text of the ScienceDaily article and a link to it.

http://www.sciencedaily.com/releases/20 … 163030.htm

Brain Disorder Suggests Common Mechanism May Underlie Many Neurodegenerative Diseases

ScienceDaily (Jan. 11, 2009) — A Mayo Clinic-led international consortium has found a mechanism that may help explain Parkinson’s and other neurological disorders.

Studying just eight families worldwide, the international team of researchers have discovered a genetic defect that results in profound depression and parkinsonism in a disorder known as Perry syndrome. Although this syndrome is exceedingly rare, the mechanism implicated in it may help explain the origins of a variety of neurodegenerative disorders, such as Parkinson’s and amyotrophic lateral sclerosis diseases, and even common depression and sleep disorders that are also hallmarks of the disorder, the researchers say.

In the study, to be published in the February issue of Nature Genetics (online January 11), the researchers report that people with Perry syndrome have mutations in a subunit of the dynactin complex (DCTN1; p150glued), which is essential to the movement of molecular “cargo” inside brain cells, or neurons. In this case, the mutations meant that the cargo was being driven on a “train” that essentially had faulty brakes. And because Perry syndrome resembles many other neurodegenerative diseases, the findings suggest breakdowns along the cell’s interior transportation grid may be a common mechanism underlying neurodegeneration.

“Understanding why distinct neurons are selectively vulnerable to neurodegeneration in different brain disorders is one of the greatest puzzles in neuroscience,” says the study’s lead investigator, Matthew J. Farrer, Ph.D., a professor of neuroscience at Mayo Clinic. “These findings suggest that trafficking of specific cargoes inside brain cells may be a general problem in a variety of neurodegenerative diseases, depression, and other disorders.”

“It points us to a unified theory of what is going wrong in many of them,” says the study’s senior author, Zbigniew K. Wszolek, M.D., professor of neurology at Mayo Clinic.

Molecules, vesicles and organelles within a cell are constantly carried via a network of crisscrossing microtubules that act like the tracks of an elaborate railroad system. Because, for the most part, neurons do not regenerate or divide as do other cells in the body, trafficking cargo efficiently over the lifetime of a neuron is fundamentally important, says Dr. Farrer.

Disruptions in this railroad system have been seen in many neurodegenerative diseases, but these problems have been generally regarded as byproducts of the disorder rather than the cause, the researchers say. These new findings may change that view, they say.

For example, in amyotrophic lateral sclerosis (ALS), a motor neuron disease also known as Lou Gehrig’s disease, the molecular motors (for example, dynein, dynactin and kinesin) that drive transport from distant nerve terminals to the cell body may become defective. In some forms of Parkinson’s disease, growing evidence indicates that the cargoes being trafficked are also misdirected by faulty signaling, due to pathogenic mutations in the leucine-rich repeat kinase 2(LRRK2) gene, Dr. Farrer says.

The findings may also shed light on other neurodegenerative disorders, the researchers say. In Alzheimer’s disease, frontotemporal dementia and progressive supranuclear palsy, for instance, the “spikes,” comprised of microtubule associated protein tau (MAPT), that normally stabilize and secure these rails tend to fall apart.

This discovery would not have been possible without a consortium of international researchers including co-authors from Canada, France, Japan, Turkey, and the United Kingdom, says Dr. Wszolek, who established the collaborative network of scientists.

Perry syndrome was first described in two unrelated Canadian families in 1975. In a study published in 2007, Dr. Wszolek, along with Swiss neurologist and visiting fellow Christian Wider, M.D., summarized the clinical features of the disease, which include early-onset parkinsonism (stiffness, slowness and rigidity), depression, severe weight loss, and increasing difficulty in breathing. Once symptoms occur, typically in the patient’s mid-40s, the disease is rapidly progressive and fatal.

In a subsequent study published in August 2008, the consortium reported that eight patients who died from the disease had substantial loss of neurons in the midbrain area known as the substantia nigra. They also found a molecular signature of Perry syndrome — “inclusions,” or clumps, of a protein known as TDP-43 — which is found in patients with frontotemporal dementia or with motor neuron disease. What these clumps represent is not known, says co-author and neuropathologist Dennis Dickson, M.D. “But they are clearly a marker of the disease process in all of these disorders, suggesting a common process is perturbed,” he says.

Mayo geneticists hypothesized that Perry syndrome may be caused by mutations within the same gene, even though families afflicted with this disorder are unrelated, and come from different continents. The disease is autosomal dominant, meaning that the chance of inheriting the disease is 50 percent if one parent carries a copy of a mutant gene. With the help and participation of eight families with Perry syndrome, the Mayo-led team set out to find the defective gene.

They determined that each family had one of five novel mutations in the DCTN1 gene, whose protein produces a large subunit of the dynactin complex known as p150glued. This protein is essential to the movement of cargo along the microtubule rails. “Curiously, the mutations all cluster in the p150glued cytoskeleton-associated protein glycine-rich domain and its ‘GKNDG’ binding motif,” Dr. Farrer says. “This region acts like a parking brake, so Perry mutations in p150glued mean that this brake is affected. It would be analogous to driving that train with faulty brakes.”

What amazed the researchers are the similarities that Perry syndrome shares with other neurodegenerative diseases. Perry mutations in DCTN1 are physically very close to a mutation previously reported in familial motor neuron disease, they say.

The deposits of TDP43 are also the same as found in motor neuron disease and in some forms of frontotemporal dementia, although they are in a different part of the brain. “With the discovery of mutations in Perry syndrome, researchers have a new means to explore the breakdown in the microtubule transport system in each of these diseases,” says Dr. Farrer. “The insides of neurons are very dynamic. Molecules and organelles are constantly being moved to where they are needed, so it makes sense that these disorders, with aging, may be caused by a progressive breakdown in this transport system.”

Understanding Perry syndrome may shed light on depression as well as metabolic syndromes, says Dr. Wszolek. Many of the patients have profound depression and about one-third of those commit suicide. Many of the patients also experience severe weight loss and sleep deprivation.

The study was funded by the Pacific Alzheimer Research Foundation of British Columbia, Canada, and the National Institute of Neurological Disorders and Strokes, which funds the Morris K. Udall Parkinson’s Disease Research Center of Excellence at Mayo Clinic, Jacksonville.

——————————————————————————–
Adapted from materials provided by Mayo Clinic.

Study of Antipsychotics in Alzheimer’s (UK)

UK research was published in the journal Lancet Neurology today. This was a study comparing those with Alzheimer’s taking antipsychotics (including Risperdal) and those with AD not taking this type of medication. In the article below, the study’s lead author is quoted as saying: ”Would I want to take a drug that slightly reduced my aggression but doubled my risk of dying? I’m not sure I would.” Here’s the text of the short article:

(This AP story was published in many places, including the New York Times.)
http://www.nytimes.com/aponline/2009/01 … Drugs.html

January 8, 2009
Study: Alzheimer’s Drugs May Raise Death Risk in Elderly
By THE ASSOCIATED PRESS

LONDON (AP) — Anti-psychotic drugs commonly used to treat Alzheimer’s disease may double a patient’s chance of dying within a few years, suggests a new study that adds to concerns already known about such medications.

”For the vast majority of Alzheimer’s patients, taking these drugs is probably not a worthwhile risk,” said Clive Ballard, the paper’s lead author, of the Wolfson Centre for Age-Related Diseases at King’s College London.

”Would I want to take a drug that slightly reduced my aggression but doubled my risk of dying? I’m not sure I would,” Ballard said.

The research was published Friday in the medical journal, Lancet Neurology.

Alzheimer’s disease is the most common cause of dementia and causes symptoms including aggression, delusions and hallucinations. Previous studies have shown anti-psychotic drugs, which can help control the aggression and hallucinations for a few months raise the risk of death in older patients with dementia. There are other side effects, including respiratory problems and stroke.

Ballard and colleagues followed 165 patients aged 67 to 100 years with moderate to severe Alzheimer’s disease from 2001 to 2004 in Britain. Half continued taking their anti-psychotic drugs, which included Risperdal, Thorazine and Stelazine. The other half got placebos.

Of the 83 receiving drugs, 39 were dead after a year. Of the 82 taking fake pills, 27 were dead after a year. Most deaths in both groups were due to pneumonia.

After two years, 46 percent of Alzheimer’s patients taking the anti-psychotics were alive, versus 71 percent of those not on the drugs. After three years, only 30 percent of patients on the drugs were alive, versus 59 percent of those not taking drugs.

In the United Kingdom and the United States, guidelines advise doctors to use anti-psychotic drugs cautiously and temporarily. But in many nursing homes in Europe and North America, up to 60 percent of patients with dementia are routinely given the drugs for one to two years.

”The drug regimen for any person with Alzheimer’s needs to be personalized,” said William Thies of the Alzheimer’s Association in the U.S. Thies was not connected to the study. ”At some points, some people will be better off with no medication.”

Simon Lovestone of the Institute of Psychiatry at King’s College in London said psychiatrists should try environmental or behavioral therapies instead of anti-psychotics.

Experts aren’t sure how the anti-psychotics increase patients’ risk of dying. But they think the drugs could be damaging to the brain and their sedative effects make patients less able to exercise and more susceptible to deadly infections.

The study was paid for by the U.K. Alzheimer’s Research Trust. Ballard reported receiving grants from various pharmaceutical companies which make drugs used to treat Alzheimer’s patients.

Preparing Ice and Utilizing Ice for a Brain Donation

Thank you for agreeing to donate your brain or your family member’s brain so that research can be enabled.  Brain donation is key to finding cures for many neurological diseases.  And it is the only way to obtain a confirmed diagnosis.

And thanks to families, hospice agencies, care facilities, caregivers, and funeral homes for making advance preparations for the brain donation.  Part of that advance preparation is organizing some bags of ice, which will be utilized to keep the family member’s head (and therefore brain) cool until the family member can reach refrigeration upon his/her passing.

Why is there a delay in getting to refrigeration?  There are multiple possible reasons for this, including:

  • family wants to spend some time with their loved one before calling the funeral home
  • if a hospice agency is pronouncing death, it make take some time for the hospice nurse to arrive
  • it may take some time for the funeral home to arrive to pick up the loved one
  • it may take some time for the funeral home to reach a place where there is refrigeration

Note that not all funeral homes in the United States have refrigeration. (In Brain Support Network’s detailed instructions for this brain donation, we indicate if there is refrigeration at the place where the brain donation work will be performed.)

PREPARATION

The family, hospice agency, care facility, or caregivers should prepare several gallon-size re-sealable Ziploc-type bags with ice.  These can be placed in a nearby freezer (at home, for example).

If hospice or a care facility is involved, the staff usually assist the family in preparation of ice bags.

If plastic bags and an ice machine are readily available, such advance preparation isn’t necessary.

Also, many care facilities or hospitals have freezer gel paks on hand.  These can certainly be used instead of bags of ice.

UTILIZATION OF ICE

Upon the passing of your loved one, please call the hospice agency, if your loved one is not a resident of a skilled nursing facility.

Our condolences to the family on your loss!

(If your family member is not on hospice and not a resident of a skilled nursing facility, usually the police and the county coroner must be notified. This can delay or make impossible the brain donation.)

Ideally, your loved one should be refrigerated as soon as possible.  It could take some time for your loved one to arrive at a place where there is refrigeration.  As soon as possible after your loved one’s passing while respecting your wishes as a family, we suggest placing plastic bags filled with ice (or frozen gel packs) around the head to keep the brain cool.

Use several gallon-size, re-sealable Ziploc-type plastic bags of ice or frozen gel packs around the head.  Place the bags or packs at both temples, on the forehead, at the top of the head (as if it were a crown), and behind the head (as if it were a pillow).  There is no need to place something on the face.  Sometimes hospice staff can use a pillowcase or hand towel to discreetly hide the plastic bags/gel packs and keep them in place.

Hospice can assist with this, if hospice staff has arrived.   Certainly care facility staff can assist with this.

Once the ice is in place, have peace of mind that your loved one’s brain is being kept cool.  Spend the time you feel you need.  How much time you have is dependent on the time of day and when the brain donation work can be performed in your family’s particular case.

If you have any questions or concerns, please contact Brain Support Network by cell phone 650-814-0848 (accepts texts) or email.

 

Man with double vision and dementia; PSP upon autopsy

The 12/15/09 issue of the journal Neurology contains an interesting case report from Case Western (Cleveland) of a 49-year-old man who was found to have the dementia form of PSP upon brain autopsy. That form of PSP is called “Richardson syndrome (RS).”

I don’t believe this man was diagnosed during life with PSP because he presented with atypical features for PSP: “young age at onset, absence of falls, and the presenting complaint of horizontal diplopia (due to vergence abnormalities). His cognitive impairment was suggestive of frontotemporal dementia. However, vertical saccades were slow at presentation.”

The report notes that the patient clapped exactly three times. This must refer to the “clap test,” which has now been discounted as a neurological test for PSP.

The patient received extensive testing, including neuro-ophthalmological testing. The clinicians have gone back through the patient’s clinical records after death to try to solve the mystery of how they missed this patient’s PSP. The researchers conclude “that careful examination of the speed (more than amplitude) of vertical saccades in patients with undiagnosed parkinsonian disorders remains the cornerstone for recognition of PSP and differentiation from other parkinsonian
disorders.”

The citation is copied below. You can purchase the article (probably costs $30). I did obtain it but think copyright law precludes copying it here.

The text refers to images of brain tissue available as a result of the brain autopsy. You can find those images at the Neurology journal’s website here:
http://neurology.org/cgi/content/full/73/24/2122/DC1 (6 images available for free)

Robin

Neurology. 2009 Dec 15;73(24):2122-4.

Evolution of oculomotor and clinical findings in autopsy-proven Richardson syndrome.

Hardwick A, Rucker JC, Cohen ML, Friedland RP, Gustaw-Rothenberg K, Riley DE, Leigh RJ.
Department of Neurology, Veterans Affairs Medical Center, Case Western Reserve University, Cleveland, OH, USA.

From the Departments of Neurology (A.H., K.G.-R., D.E.R., R.J.L.) and Neuropathology (M.L.C.), University Hospital, and Daroff-Dell’Osso Laboratory (R.J.L.), Veterans Affairs Medical Center, Case Western Reserve University, Cleveland, OH; Department of Neurology (J.C.R.), University of Louisville School of Medicine, Louisville KY; and Mount Sinai Medical Center (R.P.F.), New York, NY.

PubMed ID#: 20018641 (there’s nothing viewable at pubmed.gov on this article but you can link the the journal Neurology’s website, neurology.org, if you want to purchase the short article)