Noninvasive Quantitation of Biochemical Changes in the Human Substantia Nigra in Parkinson’s Disease: A Window into Pathogenisis

Gülin Öz, Ph.D.

University of Minnesota

Funded in December, 2006: $100000 for 1 years
LAY SUMMARY . ABSTRACT . BIOGRAPHY . HYPOTHESIS . SELECTED PUBLICATIONS .

LAY SUMMARY

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Refining MRS Imaging to Study Parkinson’s Disease Processes and Treatment Effects

Investigators will increase the sensitivity of non-invasive magnetic resonance spectroscopy (MRS) to improve the study of three Parkinson’s disease processes and how various therapies affect each of these.

Parkinson’s disease is characterized by a progressive loss in the brain’s substantia nigra of neurons that transmit dopamine to facilitate communication from one brain cell to another.  Prior research suggests that the dopamine-transmitting brain cells are damaged by “free-radicals” (oxidative stress), metabolic disturbances (mitochondrial dysfunction), and inflammation.  Efforts to prove this have been foiled, however, because the substantia nigra is so small, and conventional imaging techniques are not sensitive enough to reveal differences between patients and healthy adults.

The Minnesota researchers have already pioneered use of a “4 telsa” (instead of the conventional 2 or 3 telsa) MRS machine to quantify biomarkers of neuronal integrity and the three suspected Parkinson’s disease processes. But even greater imaging sensitivity is needed, they found, to reliably differentiate the biomarkers in patients compared to healthy volunteers.  They now will try to optimize a different pulse sequence on the magnet of a 7-telsa MRS machine to increase sensitivity four-fold. If they can, they will compare the biomarkers in Parkinson’s patients and healthy participants to see if the suspected biomarkers are valid.

Significance:  If the researchers can engineer a four-fold increase in MRS sensitivity, their research would profoundly contribute to studies of Parkinson’s disease processes, provide for earlier diagnosis, and facilitate assessments of the effectiveness of various therapies in preventing or arresting neural degeneration in this disease.

ABSTRACT

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Noninvasive Quantitation of Biochemical Changes in the Human Substantia Nigra in Parkinson’s Disease: A Window into Pathogenisis

Parkinson’s disease (PD) is characterized by progressive loss of dopaminergic neurons in the substantia nigra (SN). Many lines of evidence suggest that oxidative stress, mitochondrial dysfunction, and inflammation are crucial factors that contribute to this neuronal loss. However, there are no established methods available to study these cellular and biochemical processes in the SN of individuals who have PD. This is primarily due to the small size of the SN and the lack of sensitivity and resolution of conventional imaging techniques. Development of non-invasive, quantitative, and reliable methods to assay oxidative stress, mitochondrial dysfunction and inflammation would not only help determine the validity of pathogenic mechanisms for PD, but also facilitate the evaluation of experimental anti-parkinsonian drugs that target these biochemical events.

We have demonstrated the feasibility of high field (4 tesla) magnetic resonance spectroscopy (MRS) to quantify markers of all three purported pathogenic processes, as well as markers of neuronal integrity, in the SN of healthy volunteers and individuals with PD.  Further increases in sensitivity are necessary to reliably assess differences between patients and control participants. Therefore, we will use a higher field MRI instrument (7 tesla) and optimize a different pulse sequence on this magnet, which will increase the sensitivity by up to 4-fold.  We will then study the SN neurochemical profiles of healthy controls and patients with PD with the optimized technique. We expect to observe alterations in neuronal markers, as well as indicators of oxidative stress, mitochondrial dysfunction, and inflammation. Neurochemical concentrations will also be correlated with the severity of clinical features of PD.

Therefore, we are proposing that high field MRS technology will be useful to assess neuronal status in the SN, along with various pathogenic factors that are thought to contribute to cell loss in PD. If the proposed biomarkers are validated, they will be valuable for testing therapeutic agents that target the pathogenic mechanisms we propose to assay. For example, present drug research focuses on compounds such as coenzyme Q10, creatine, and anti-inflammatory agents, which may be beneficial through their effects on oxidative stress, mitochondrial function and inflammatory mechanisms, respectively. Our long term goal is to utilize the high field MRS method as an objective means to assess the effects of these agents.

INVESTIGATOR BIOGRAPHIES

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Gülin Öz, Ph.D.

Assistant Professor of Radiology, University of Minnesota

HYPOTHESIS

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Hypothesis:
The neurochemical profile of the substantia nigra (SN) of patients with Parkinson’s disease (PD) as measured by high field magnetic resonance spectroscopy (MRS) will differ from that of healthy controls, in that glutathione will be lower due to oxidative stress, lactate will be higher due to mitochondrial dysfunction, the gliosis markers myo-inositol and glutamine will be higher due to inflammation (glial activation), and N-acetylaspartate and glutamate will be lower due to neuronal loss/damage.

Goals:
To develop non-invasive, quantitative, and reliable methods to assay neuronal status along with the major biochemical events thought to be involved in PD pathogenesis, namely oxidative stress, mitochondrial dysfunction, and inflammation, directly in the substantia nigra, the primary site of involvement in this neurodegenerative disease.  Specifically, we will implement and optimize methodology for measuring 1H MR spectra from the SN at the magnetic field of 7 tesla (T); and with this optimized methodology we will quantify the neurochemical profile of the SN of healthy volunteers and patients with PD and compare glutathione, lactate, glutamine, myo-inositol, NAA, and glutamate levels in patients vs. controls.

Methods:
Goal 1a) We will optimize a pulse sequence developed in our center (localization by adiabatic selective refocusing, LASER) (Garwood and DelaBarre, 2001) for achieving the best sensitivity to quantify the highest number of neurochemicals in the SN. These studies will be carried out with phantoms and healthy volunteers.

Goal 1b) We will recruit patients with idiopathic PD with mild-moderate severity (Hoehn & Yahr Stage II – III) and age-matched control participants.   Localized 1H MR spectra will be acquired from volumes-of-interest of ~1 ml centered on the unilateral SN using the LASER sequence with optimized parameters.  Absolute concentrations of neurochemicals will be determined using an automated deconvolution program (LCModel).

SELECTED PUBLICATIONS

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Öz G., Terpstra M., Tkáč I., Aia P., Lowary J., Tuite P.J., and Gruetter R.  Proton MRS of the unilateral substantia nigra in the human brain at 4 tesla: detection of high GABA concentrations. Magn Reson Med. 2006 Feb;55(2):296-301.

Öz G., Tkáč I., Charnas L.R., Choi I.Y., Bjoraker K.J., Shapiro E.G., and Gruetter R. Assessment of adrenoleukodystrophy lesions by high field MRS in non-sedated pediatric patients. Neurology. 2005 Feb 8;64(3):434-41.