DAT-SPECT: useful for DLBvAD, not useful for MSA, PSP, CBD

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This recently-published article touches upon the four disorders in our group.

It’s a review article is about the use of DAT-SPECT — dopamine transporter SPECT scans — in diagnosing movement disorders. The authors have done a great job in reviewing all the data and then presenting understandable one-sentence conclusions, which I will now share…

For MSA, PSP, and CBD, the authors conclude: In “clinical practice, DAT-SPECTs are not useful in differentiating between PD and atypical parkinsonian syndromes (MSA, PSP, CBD).”

For DLB, the authors conclude: “DAT-SPECT cannot discriminate between PD/PD-dementia and DLB but can be very useful in the differential diagnosis between DLB and Alzheimer disease and can also be of some value in the differential diagnosis between DLB and vascular dementia.”

I remember learning back in 2008 that there was some type of legal issue with bringing SPECT scans to the US, though they are already widely used in Europe. SPECT imaging is important for some disorders (such as DLB) so it’s been frustrating that SPECT imaging is not approved for use in the US except in a few research settings. In 2008, there was a Q&A with Dr. Mark Stacy from Duke about this:

“Question: Why are SPECT scans not available in the US?
Answer: Because of corporate changes. GE bought Amersham (sp?). 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.”

Recently, I asked Dr. Hubert Fernandez (on NPF’s “Ask the Doctor” Forum) about the status of bringing DAT-SPECT scans to the US. He first explained what a DAT ligand is and then answered the question:

“DAT (dopamine transporter) is a type of ligand (vehicle or medium) to conduct the SPECT scan. [It] ‘tags’ dopamine. It is important that the medium used is the correct one. Good examples are altropane or B-CIT….these are ligands that are used for SPECT scans to evaluate for PD.

Yes, for now, they DAT SPECT scans are not commercially available….but soon they they will be. One of the companies that manufactures a DAT ligand has received an ‘approvable letter’ from the FDA.”

OK, that’s probably all any of you want to know about DAT-SPECT imaging.

I’ve copied the article’s abstract and a few excerpts below, if any of you want to go further…

Robin

Journal of Neurology, Neurosurgery & Psychiatry. 2010 Jan;81(1):5-12.

The role of DAT-SPECT in movement disorders.

Kägi G, Bhatia KP, Tolosa E.
Sobell Department of Motor Neuroscience and Movement Disorders, Institute of Neurology, University College London, National Hospital for Neurology and Neurosurgery, London, UK.

Dopamine transporter (DAT) imaging is a sensitive method to detect presynaptic dopamine neuronal dysfunction, which is a hallmark of neurodegenerative parkinsonism. DAT imaging can therefore assist the differentiation between conditions with and without presynaptic dopaminergic deficit.

Diagnosis of Parkinson disease or tremor disorders can be achieved with high degrees of accuracy in cases with full expression of classical clinical features; however, diagnosis can be difficult, since there is a substantial clinical overlap especially in monosymptomatic tremor (dystonic tremor, essential tremor, Parkinson tremor).

The use of DAT-SPECT can prove or excludes with high sensitivity nigrostriatal dysfunction in those cases and facilitates early and accurate diagnosis.

Furthermore, a normal DAT-SPECT is helpful in supporting a diagnosis of drug-induced-, psychogenic- and vascular parkinsonism by excluding underlying true nigrostriatal dysfunction.

This review addresses the value of DAT-SPECT and its impact on diagnostic accuracy in movement disorders presenting with tremor and/or parkinsonism.

PubMed ID#: 20019219 (see pubmed.gov for abstract only)

———-

Excerpts (in case you didn’t get enough already):

“Atypical parkinsonism (MSA, PSP, CBD)
The differentiation of atypical parkinsonian disorders from PD and between each other can raise considerable difficulties, particularly in early disease stages. This difficulty is reflected in clinicopathological studies where atypical parkinsonism accounts for a large part of misdiagnosis in PD. MSA, especially the parkinsonian subtype (MSA-P), can initially be very difficult to distinguish from PD before more specific symptoms like pronounced autonomic involvement, laryngeal stridor or lack of response to dopaminergic therapy occur. The same is true for the parkinsonian type of PSP (PSP-P) in which the more disease-specific signs and symptoms such as supranuclear vertical gaze palsy and imbalance with falls occur. Also, corticobasal degeneration (CBD) can initially easily be mistaken as PD because of its marked asymmetrical akinetic-rigid syndrome before apraxia, myoclonus and cognitive problems occur. A faster disease progression and a poor responsiveness to levodopa are common features in atypical forms and is explained by the pre- and postsynaptic dopaminergic degeneration. However,
some responsiveness to levodopa is not uncommon in early MSA-P or PSP-P. Previously, several studies have been carried out to establish the value of DAT-SPECT for the differentiation between PD and atypical PD. It has been shown that DAT-SPECT is sensitive in detecting presynaptic nigrostriatal degeneration in PD and atypical PD but not useful in the differential diagnosis of PD and atypical PD.”

“The amount and pattern of reduced striatal DAT binding in MSA have been shown to be in the range of PD with a more pronounced loss of DAT binding in the posterior putamen compared with the caudate to be typical for both. Asymmetry of DAT binding loss tends to be more pronounced in PD, and progression is faster in MSA compared with PD. PET and DAT-SPECT studies have shown that even clinically pure forms of MSA-C have some decrease in DAT binding but less compared with MSA-P or PD. This finding could be of some diagnostic impact in the differential diagnosis of MSA-C to idiopathic late-onset cerebellar ataxia (ILOCA). For separating MSA from PD,
other techniques such as voxelwise analysis of DAT-SPECT combined DAT/D2 receptor SPECT (IBZM, Epidepride,
Iodolisuride and IBF) or D2 PET (raclopride) can provide more information, although D2 receptor binding imaging methods are influenced by dopaminergic therapy and are therefore most useful in drug-naive patients. In drug-naive PD, D2 binding exceeds normal levels because of D2 receptor upregulation, whereas D2 binding is reduced in MSA early on because of postsynaptic degeneration. PET studies may contribute in the differential diagnosis of these entities. Striatal metabolic studies using FDG have shown to be of value in the differential diagnosis of atypical parkinsonism with hypermetoablism in the dorsolateral putamen in PD, bilateral hypometabolism in the putamen in MSA and hypometabolism of the brainstem and the middle frontal cortex in PSP. In CBD, unlike PSP or PD,
unilateral balanced (caudate/putamen) reduction in tracer uptake has been observed. In addition, cardiac imaging with MIBG has shown changes consistent with heart denervation in patients with PD which are not present in patients with MSA or PSP.”

“DAT-SPECT is also of limited value in the differential between PD and PSP, although PSP seem to have a more
symmetrical and profound DAT loss in the whole striatum, whereas in PD the posterior part of the putamen shows more loss of DAT density compared with the anterior part and the caudate.”

“DAT loss in CBD is in the same range as it is in PD and atypical PD, although DAT loss is much more asymmetrical and less pronounced than that seen in MSA and PSP. D2 SPECT seems to be of less value compared with MSA and PSP because D2 binding in CBD is more often in normal range than it is in MSA and PSP.”

“In conclusion, DAT-SPECT imaging does not help to differentiate between the neurodegenerative parkinsonian disorders. Hence, in clinical practice, DAT-SPECTs are not useful in differentiating between PD and atypical parkinsonian syndromes (MSA, PSP, CBD).”

“Dementia with Lewy bodies
In dementia with Lewy bodies (DLB), the extent of DAT loss in the striatum is in the range of PD and therefore not useful in the differential of PD and atypical PD. Neuropathological data suggest that 50­60% of dementia in people aged 65 or older is due to Alzheimer disease, with a further 10­20% each attributable to DLB or vascular cognitive impairment. Operationalised clinical diagnostic criteria have been agreed for all of these syndromes, but even in specialist research settings, they have limited accuracy when compared with neuropathological autopsy findings. Distinguishing Alzheimer disease from DLB is clinically relevant in terms of prognosis and appropriate treatment. A striking biological difference between DLB and Alzheimer disease is the severe nigrostriatal degeneration and consequent DAT loss that occurs in DLB, but not to any significant extent in Alzheimer disease. Several imaging
studies have shown that DAT imaging improves diagnostic accuracy with a sensitivity of 78% and a specificity of up to 94% in the separation between DLB and AD. Most of these studies have used clinical diagnosis as the gold standard, and the results have to be taken with some caution. One study with 20 cases with pathologically proven dementias (DLB/non-DLB) and with an FP-CIT SPECT at initial clinical workup showed that the DAT imaging substantially enhanced the accuracy of diagnosis of DLB by comparison with clinical criteria alone. Abnormal DAT imaging has therefore also been included as a suggestive feature in the DLB consensus criteria in 2005.”

“In conclusion, DAT-SPECT cannot discriminate between PD/PD-dementia and DLB but can be very useful in the differential diagnosis between DLB and Alzheimer disease and can also be of some value in the differential diagnosis between DLB and vascular dementia.”

The 6 R’s of Managing Difficult Behavior (from The 36-Hour Day)

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The Johns Hopkins Health Alert from Monday may be of interest to those dealing
with challenging behavior. It’s on “The 6 R’s of Managing Difficult Behavior,”
according to Dr. Peter Rabins and Nancy Mace, as discussed in their book The
36-Hour Day, which I highly recommend to anyone dealing with dementia.

The 6 R’s are:
* Restrict
* Reassess
* Reconsider
* Rechannel
* Reassure
* Review

You can sign up for these health alerts (they come to your email) here:
http://www.johnshopkinshealthalerts.com

Robin

http://www.johnshopkinshealthalerts.com/alerts/memory/JohnsHopkinsHealthAlertsMemory_3178-1.html

The 6 R’s of Managing Difficult Behavior
Johns Hopkins Health Alert: Memory
Dated 1/4/10

Restrict, Reassess, Reconsider, Rechannel, Reassure, Review

In their groundbreaking book on Alzheimer’s caregiving — The 36-Hour Day — Peter Rabins, M.D. (author of the Johns Hopkins Memory White Paper) and Nancy Mace discuss the six R’s of managing difficult behavior in people with dementia. Here they are…

People with dementia often exhibit behaviors that are frustrating, embarrassing, and sometimes even dangerous to the caregiver and others. These may include angry outbursts, agitation, aggression, wandering, vocalizations, hoarding or hiding things, and inappropriate sexual behavior.

For many caregivers, these difficult behaviors are the most challenging and exhausting aspect of caring for a person with dementia. Unfortunately, the available medications to treat Alzheimer’s disease have little effect on behavioral problems.

Here are Dr. Rabins’ six coping strategies:

Dementia Strategy 1 — Restrict. First, calmly attempt to get the person to stop the behavior, especially if the behavior is potentially dangerous.

Dementia Strategy 2 — Reassess. Consider what might have provoked the behavior. Could a physical problem (toothache, urinary tract infection, osteoarthritis) be behind the agitation or anger? Is a particular person or the noise level in the room triggering the negative reaction? Could the time of day and fatigue be contributing to the problem?

Dementia Strategy 3 — Reconsider. Put yourself in the dementia patient’s shoes. Try to imagine what it must be like to not understand what is happening to you or to be unable to accomplish a simple task. Consider how frustrating or upsetting the current situation or environment might be for a person with dementia.

Dementia Strategy 4 — Rechannel. Try to redirect the behavior to a safer, less disruptive activity. For example, if the person constantly disassembles household items, try finding simple unused devices, such as an old telephone or a fishing reel, that can be taken apart and put back together repeatedly. For someone who hoards or hides things, put away valuables and replace them with an array of inexpensive items.

Distraction often works well to curtail disruptive repetitive behaviors and restlessness. For example, try asking the person you’re caring for to “help” with simple tasks, such as holding spoons or potholders while you cook.

Dementia Strategy 5 — Reassure. The demented person’s brain injury and the resulting confusion and frustration can lead to anger, anxiety, and outright fear in certain situations. Calmly reassure the person that everything is okay and that you will continue to take care of him or her.

Dementia Strategy 6 — Review. After an unsettling experience with your loved one, take time to review how you managed the problem and what you might have done differently. Think about what may have triggered the problem, how it might have been avoided, and what you might try the next time a similar situation arises.

It also helps to create a patient-friendly environment. This might include soothing music in the background; pictures, words, or arrows to help orient the person in the house; or a secure place to sit outside or walk in the backyard.

Maintaining Hope (in living with Parkinson’s)

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This short article on “Maintaining Hope” while living with Parkinson’s Disease was
published in the Fall 2005 APDA (American Parkinson Disease Association) Newsletter.
Though it’s about Parkinson’s Disease, the article certainly applies to any disorder.

Robin

http://www.apdaparkinson.org/data/NewsLetterUpload/APDAFal2005newest.pdf –> article on page 1

Maintaining Hope
by Linda O’Connor, LCSW
Coordinator APDA I&R Center, Los Angeles, CA
American Parkinson Disease Association
Fall 2005 Newsletter

In my work as the Coordinator of the Los Angeles APDA Information and Referral Center at Cedars-Sinai Hospital, I
have the opportunity to talk with people diagnosed with Parkinson’s disease (PD) and their family members every day, and one of the most significant aspects of our contact often centers on the subject of “hope”. Sometimes it is spoken, and often unspoken, but the question of hope is always present in some way.

Living with PD is challenging, both physically and emotionally for the person who has been diagnosed, as well as for family members. In difficult times it becomes vital to have something to hold on to, and in my opinion, one of the best things is hope. Because having hope can be such a powerful tool to assist with coping, it is certainly worth
further exploration and understanding.

Defining Hope
According to the dictionary, hope is: “A desire accompanied by expectation of or belief in fulfillment; also expectation of fulfillment or success.” Richard Lazarus, a psychologist who has done a great deal of study and writing on hope, defines it this way: “To hope is to believe that something positive, which does not presently apply to one’s life, could still materialize, and so we yearn for it. Although desire is an essential feature, hope is much more than this because it requires the belief in the possibility of a favorable outcome.”

The fact that having the diagnosis of PD brings with it so much uncertainty, and because you don’t know absolutely for sure what will happen next, this creates the possibility that something good may happen, and that possibility makes room for hope.

No one’s future is absolutely foretold, so while there may be reason to fear, there is also great reason to hope.

Hope as a Coping Process
Maintaining a hopeful attitude can be an extremely helpful coping strategy. First it produces action. Studies have shown that hope can galvanize efforts to seek improvement of an unfavorable situation. Without hope we are unlikely to act on our own behalf. Hope combines yearning for something better with the belief that our actions could help to bring about the outcome we want.

Hope is why people seek information about Parkinson’s disease and its treatment. Hope is why people become actively involved in getting the best treatment possible. Hope is why people exercise, concentrate on good nutrition and focus on stress management. Hope is why people connect with each other for support or do advocacy work or enroll in clinical trials. Hope is why people don’t give up, even in some of the most difficult situations. It keeps us engaged with life.

The second way that hope aids coping is that it serves as a vital resource against despair. The best defense we have against despair and the depression that accompanies it is hope.

Cultivating Hope
Because hope partly involves our thought process, it is possible to make very deliberate, conscious decision to be hopeful. Now this may not happen overnight, and it may not work every single day, especially if you’re having a particularly bad day, BUT… it is worth trying to focus on maintaining an overall hopeful attitude as much as possible.

“The Placebo Effect” (in Parkinson’s)

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In 2009 I attended a Stem Cell Awareness Day at The Parkinson’s Institute in Sunnyvale. All of the MDs were asked about stem cell treatment for Parkinson’s Disease, and why some people who go to China or Germany or where ever for stem cell therapy report improvements.

The MDs all pointed to the placebo effect. And they said that the bigger the intervention, the bigger the placebo effect. One example of this was a UCSF gene therapy trial from 2008 where the placebo group (who received no surgery but did get a hole drilled in their skull) had greater motor improvement in comparison to the treatment group (who got the gene therapy surgery).

Dr. Melanie Brandabur of The PI also noted that the placebo effect is not psychological alone. She said that the brains of Parkinson’s patients who receive these experimental treatments are somehow able to produce a bit more dopamine, demonstrating physiological changes.

A few people with multiple system atrophy have reported on the online MSA-related support groups that they’ve gone outside the US for stem cell therapy. Only one person has reported sustained good results. One gentleman recently reported that he concluded his wife experienced a placebo effect after her stem cell treatment in Germany.

Here’s an article about the placebo effect — a general look at the effect and then a specific look at how it occurs in Parkinson’s Disease drug trials.

Robin

http://www.apdaparkinson.org/data/NewsLetterUpload/APDAFal2005newest.pdf –> article on pages 10-11

Drugs Trials — The Placebo Effect
By J. Stephen Fink, MD, Ph.D.
American Parkinson Disease Associatio Newsletter
Fall 2005

A medication may have several effects on a patient. Some effects may be directly related to the medication’s effect on the body’s functions, which is called the pharmacological effect.

Another effect of a medication may not be linked directly to the medicine’s pharmacological effect. This is called the placebo effect. A placebo effect can be observed when a pharmacologically inactive substance is administered.

What is the placebo effect, what does the placebo effect have to do with the process of developing new treatments or new medications in controlled clinical trials, what is the importance of the placebo effect for clinical trials in Parkinson’s disease?

The word placebo comes from the Latin verb “placere,” that means, “to please.” Placebo is an inactive treatment and the placebo effect is the effect (usually beneficial) resulting from the administration of an inactive substance. When a patient receives any treatment (whether it is active or not) there may be a beneficial effect experienced by the patient just because there is an expectation of benefit. Placebo effects can result simply from contact with doctors or other health care providers, even in the mere act of interviewing or examining a patient. There may also be beneficial effects of additional treatment or improved care provided during the clinical trial of a new medication.

In addition to expectation of benefit, other contributors to this improvement in patients’ symptom scores may include the tendency for patients to enter trials when their symptoms are worse, and “bias” in the rater’s scoring of patients symptoms.

The beneficial effect resulting from the act of receiving treatment may be quite powerful and long lasting. For example, in some studies of asthma and pain, there was improvement of 30-40 per cent in subjects given placebo
(inactive) medications. The beneficial effect of receiving any treatment is not limited to medications, as the
expectation of benefit alone may lead to improvement in symptoms after surgical procedures as well.

The placebo effect can interfere with the assessment of whether a new medication or treatment is really beneficial.
Therefore, when new medications are tested, they are commonly compared to an inactive treatment (placebo); this is a placebo-controlled trial.

When neither the patient nor the examiner knows whether the patient is receiving active treatment or placebo, the
trial is referred to as “double-blind.” When the subjects are assigned to active treatment or placebo groups by chance, this is called a randomized trial. Randomized, double blind, placebo-controlled trials offer the most effective way to control for the placebo effect and have become the “gold-standard” in clinical trial design for assessing new drugs or treatments. For a new medication or therapy to be considered effective, it must be shown to be better than a placebo in a double-blind, randomized, placebo-controlled trial. Sometimes therapies that are thought to be effective are no better than placebo when tested in this type of trial.

Long lasting placebo effects have been reported in Parkinson’s disease. In some medication trials improvement in motor scores of 20-30 per cent in patients assigned to the placebo group has been observed for up to 6 months. Similarly, improvement and deterioration in Parkinson’s disease patients have been observed after the introduction and discontinuation, respectively, of placebo medication.

Placebo effects appear to be particularly evident in the clinical trials of surgical therapies. In the double blind, clinical trial of human fetal transplantation in Parkinson’s disease conducted by Fahn, Freed and colleagues, the control group received an “imitation” surgical procedure. Several of the patients in the control group rated themselves improved one year later. Similarly, 30 per cent improvement in motor scores in the placebo control (imitation surgery) patients was observed in the double-blind trial of porcine mesencephalic tissue. In this trial, improvement in the control group lasted at least 18 months, longer than had been previously observed in clinical trials of medications, suggesting that placebo effects may be stronger in clinical trials of surgical therapies.

What causes the placebo effect? It is not possible to test adequately for placebo effects in laboratory animal experiments because animals are not known to have responses to placebo. It has been assumed that the placebo
response is not mediated directly through a physical or chemical effect of treatment. However, a remarkable study by Jon Stoessl and colleagues demonstrated that the placebo effect in Parkinson’s patients was accompanied
by a release of brain dopamine from the remaining midbrain dopaminergic cells. This suggests that the improvement in motor function that is observed in the placebo groups of clinical trials in Parkinson’s patients might be due, in part, to actual physiological changes in the damaged brain dopamine nerve cells.

In summary, the placebo effect is important in the testing of new medications for Parkinson’s disease. It dictates
the design of clinical trials of new medications by the inclusion of placebo groups. The placebo effect might be considered to “benefit” those Parkinson’s disease patients who join clinical trials and are assigned to the placebo group, as they may demonstrate improvement in symptoms. Indeed, some of this improvement in symptoms in the placebo group may actually be due to beneficial changes in brain dopaminergic nerve cells.

This perspective underscores the often-spoken adage at Parkinson’s disease centers: “One of the best things to do when a patient first learns of the diagnosis of Parkinson’s disease is to join a clinical trial.” Among the many benefits of such participation may be the placebo effect!

Adapted from “The Placebo Effect in Clinical Trials” by Stephen Fink, MD, Ph.D. in the Summer 2005 Young Parkinson’s Newsletter.

New LBD Caregiver Blog

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This blog was started in November 2009 by Gilli whose 80-year-old mother may have Lewy Body Dementia. I believe they live in the UK. The family is dealing with many behavioral issues. The mother is currently in a hospital; I don’t know if this is a skilled nursing facility or a psychiatric ward.

Here’s a brief excerpt:
“It seems that this illness became noticeable in Sept 2008 after going on a cruise… A brief spell in hospital followed a ‘passing out’ not unconscious, aware of what was said around her but not responding to anyone.Various tests followed …perhaps a small stroke or TIA it was thought, perhaps vascular dementia but as time has passed it is thought that it is Lewy Body dementia. ”

See:
http://mummeandlewybodydisease.blogspot.com/

Robin