Category Archives: PSP

FDG-PET for differentiating PD, PSP, and MSA

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This article on the use of FDG-PET in differentiating PD, MSA, and PSP was published today in The Lancet Neurology. I haven’t had a chance to wade through all of the article yet but it seems to be one of the better articles we’ve seen lately on PSP and MSA. 167 patients in the NY area participated in the study. Only 9 of these patients have died and donated brain tissue thus far. So I’m not sure how “real” the diagnostic accuracy percentages are. And the diagnosis of CBD was not part of the study.

Below, I’ve copied a HealthImaging.com article on this research as well as the abstract.

Robin

The Lancet Neurology, Early Online Publication, 11 January 2010.

Differential diagnosis of parkinsonism: a metabolic imaging study using pattern analysis

Chris C Tang MD, Kathleen L Poston MD, Thomas Eckert MD, Andrew Feigin MD, Steven Frucht MD, Mark Gudesblatt MD, Vijay Dhawan PhD, Martin Lesser PhD, Jean-Paul Vonsattel MD, Stanley Fahn MD, David Eidelberg MD

Summary

Background
Idiopathic Parkinson’s disease can present with symptoms similar to those of multiple system atrophy or progressive supranuclear palsy. We aimed to assess whether metabolic brain imaging combined with spatial covariance analysis could accurately discriminate patients with parkinsonism who had different underlying disorders.

Methods
Between January, 1998, and December, 2006, patients from the New York area who had parkinsonian features but uncertain clinical diagnosis had fluorine-18-labelled-fluorodeoxyglucose-PET at The Feinstein Institute for Medical Research. We developed an automated image-based classification procedure to differentiate individual patients with idiopathic Parkinson’s disease, multiple system atrophy, and progressive supranuclear palsy. For each patient, the likelihood of having each of the three diseases was calculated by use of multiple disease-related patterns with logistic regression and leave-one-out cross-validation. Each patient was classified according to criteria defined by receiver-operating-characteristic analysis. After imaging, patients were assessed by blinded movement disorders specialists for a mean of 2·6 years before a final clinical diagnosis was made. The accuracy of the initial image-based classification was assessed by comparison with the final clinical diagnosis.

Findings
167 patients were assessed. Image-based classification for idiopathic Parkinson’s disease had 84% sensitivity, 97% specificity, 98% positive predictive value (PPV), and 82% negative predictive value (NPV). Imaging classifications were also accurate for multiple system atrophy (85% sensitivity, 96% specificity, 97% PPV, and 83% NPV) and progressive supranuclear palsy (88% sensitivity, 94% specificity, 91% PPV, and 92% NPV).

Interpretation
Automated image-based classification has high specificity in distinguishing between parkinsonian disorders and could help in selecting treatment for early-stage patients and identifying participants for clinical trials.

Funding
National Institutes of Health and General Clinical Research Center at The Feinstein Institute for Medical Research.

http://www.healthimaging.com/index.php? … e&id=20154

TOP STORIES
Lancet: FDG-PET could distinguish between Parkinsonian disorders
Written by Editorial Staff, HealthImaging.com
January 11, 2010

FDG-PET imaging-based classification has high specificity to differentiate individual patients with idiopathic Parkinson’s disease, multiple system atrophy and progressive supranuclear palsy and could help in selecting treatment for early-stage patients and identifying participants for clinical trials, according to research published online Jan. 11 in Lancet Neurology.

David Eidelberg, MD, director of the center for neurosciences at the Feinstein Institute for Medical Research in Manhasset, N.Y., and colleagues assessed whether metabolic brain imaging combined with spatial covariance analysis could accurately differentiate between patients with Parkinsonism who had different underlying disorders.

In the study, 167 patients who had Parkinsonian features but uncertain clinical diagnosis had an 18F-FDG PET scan. The researchers developed an automated image-based classification procedure to differentiate individual patients with Parkinsonian disorders and the accuracy was assessed by comparison with the final clinical diagnosis.

Eidelberg said that out of the 167 patients assessed, image-based classification for idiopathic Parkinson’s disease had 84 percent sensitivity, 97 percent specificity, 98 percent positive predictive value (PPV) and 82 percent negative predictive value (NPV).

Eidelberg and colleagues found that imaging classifications were also accurate for multiple system atrophy (85 percent sensitivity, 96 percent specificity, 97 percent PPV, and 83 percent NPV) and progressive supranuclear palsy (88 percent sensitivity, 94 percent specificity, 91 percent PPV and 92 percent NPV).

In an accompanying commentary, Angelo Antonini, MD, at IRCCS San Camillo, Venice and Parkinson Institute in Milan, Italy, wrote that the “clinical and research relevance of these findings should not be underestimated. Neuroprotective and disease-modifying drug research is intensifying and results mostly rely on accurate early diagnosis.”

“The excellent specificity and PPV of the imaging classification makes this test suitable for diagnostic use rather than as a screening tool,” Eidelberg noted.

“Although imaging might be cost effective for early diagnosis, I expect that these procedures will find their natural application in the identification of suitable candidates for drug trials or complex surgical procedures (example, deep brain stimulation, stem-cell transplantation or fetal tissue transplantation). However, additional blinded, prospective, multicenter studies will first be needed to confirm the accuracy of this pattern-based categorization procedure,” Antonini concluded.

Last updated on January 11, 2010 at 12:48 pm EST

Man with double vision and dementia; PSP upon autopsy

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PSP folks –

This is an interesting case report 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.”

I note that the patient clapped exactly three times. This must refer to the “clap test,” which has now been greatly 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 below.

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)

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)

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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.”

Hospice RN Bill Carroll’s great article on when hospice should be contacted

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When CurePSP was the Society, it published at least twice hospice nurse Bill Carroll’s article on hospice in the PSP Advocate (now called the CurePSP Magazine). Here’s the text of his great article.  (On the PSP Forum, Bill goes by 104fm.)

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 (1st issue)

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 well-trained 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

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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
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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)