Georges El Fakhri, Ph.D.

Funded in December, 2004: $100000 for 4 years

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Using Imaging for Early Diagnosis of Parkinson’s and Diffuse Lewy Body Disease

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A Novel Imaging Approach for Early Diagnosis of Parkinson's and Diffuse Lewy Body Diseases

Hypothesis:
The distinction between patients with Parkinson's disease who have concomitant Alzheimer disease (generally known as the Lewy Body Variant of AD [LBV-AD]) and those with diffuse Lewy Body Disease (DLBD) is very difficult to make at the time when cognitive impairment is first evident.  The origin of the cognitive impairment in these patients is also unclear.  Assessing brain perfusion and neurotransmission simultaneously using simultaneous dual isotope SPECT would yield valuable insight into the two diseases and, potentially, make it possible to discriminate between the two dementia categories at an early stage.  Such studies would also allow us to relate the quantitative estimates of brain perfusion and pre-synaptic dopamine function to quantitative measures of motor and cognitive function.

Goals:
The overall goal of the study will be to determine how well measures of dopamine function and blood perfusion derived from quantitative simultaneous dual-tracer SPECT correlate with clinical manifestations of PD and measures of cognitive ability, both global and particular.

The ultimate goal of this work is to optimize quantitative dual isotope SPECT imaging for the purpose of detecting the earliest disease-related changes in the brain.  This will lead to an improved understanding of the natural history of neurological diseases such as PD and DLBD.  Furthermore, simultaneous dual-isotope SPECT imaging has the potential to become a convenient, safe, and accurate technique for monitoring disease progression or response to therapy.

Methods:
Because the emission energies of photons from the two radio-isotopes that are attached to the tracers, ^99mTc and ¹²³I, are very close, discrimination between them on the basis of energy is extremely difficult.  We will extend a method we have recently developed that makes possible separation of these two isotopes to the simultaneous imaging of blood perfusion and post-synaptic dopamine function in PD patients.  Our methodology will also address correction of the effects of other physical processes, such as attenuation and limited and variable spatial resolution, that compromise the accuracy of the images.

We will apply this technique to simultaneous imaging of pre-synaptic dopamine function (¹²³I-altropane) and perfusion (^99mTc-HMPAO) in 40 PD patients with cognitive impairment and 20 PD patients without cognitive impairment.  Subjects will have a UPDRS and a brief neuropsychological battery, as well as simultaneous ¹²³I-altropane / ^99mTc-HMPAO SPECT scans.  The overall goal of the analyses will be to determine, using correlation analysis, how well measures of dopamine function and blood perfusion derived from quantitative simultaneous dual-tracer SPECT correlate with clinical manifestations of PD, as measured by the UPDRS, and measures of cognitive ability, both global (the Blessed score) and particular (the tests in the neuropsychological battery, including tests of memory, conceptualization, spatial function, and attention).

We have demonstrated the feasibility and utility of dual isotope SPECT for differential diagnosis of idiopatic Parkinson’s disease (IPD) and multiple system atrophy (MSA).  Simultaneous ^99mTc-ECD/¹²³I-FP-CIT studies were performed in 9 normal controls, 5 IPD, and 5 MSA patients.  Projections were corrected for scatter, cross-talk, and high-energy penetration using artificial neural networks and five dimensional factor analysis, and iteratively reconstructed while correcting for patient-specific attenuation and variable collimator response.  Perfusion and dopamine transporter (DAT) function were assessed using voxel-based statistical parametric mapping (SPM2) and volume of interest (VOI) quantitation.  DAT binding potential (BP) and asymmetry index (AI) were estimated in the putamen (PUT) and caudate nucleus (CN).  Striatal BP was lower in IPD (55%) and MSA (23%) compared to normal controls, and in IPD compared to MSA (p<0.05).  AI was greater for IPD than for MSA and controls both in CN and PUT (p<0.05).  There was significantly decreased perfusion in the left+right nucleus-lentiformis in MSA compared to IPD and controls (p<0.05). Our work shows that dual-isotope studies are both feasible in and promising for the diagnosis of parkinsonian syndromes. 

This work has led to NIH funding for the principal investigator under a jointly funded RO1 by the NIA and NIBIB (EB005876: “Quantitative Simultaneous Dual Isotope SPECT”), as well as grant funding from the American Heart Association under Grant in Aid (GIA655909T: “Absolute Quantitation of Myocardial Blood Flow Using Rb-82 PET”).

El Fakhri G., Sitek A., Zimmerman R.E., and Ouyang J.  Generalized five-dimensional dynamic and spectral factor analysis. Med Phys. 2006 Apr;33(4):1016-24.

El Fakhri G., Ouyang J., Zimmerman R.E., Fischman A.J., and Kijewski M.F.  Performance of a novel collimator for high-sensitivity brain SPECT. Med Phys. 2006 Jan;33(1):209-15.

El Fakhri G., Habert M.O., Maksud P., Kas A., Malek Z., Kijewski M.F., and Lacomblez L.   Quantitative simultaneous (99m)Tc-ECD/123I-FP-CIT SPECT in Parkinson's disease and multiple system atrophy.  Eur J Nucl Med Mol Imaging. 2006 Jan;33(1):87-92.