Functional Brain Imaging Functional brain imaging has emerged as a crucial tool to understand and to assess new therapies for neurological disorders. IND specializes in neuroimaging and is conducting several large multi-center studies aimed at understanding the progression of Parkinson’s disease and Huntington’s disease. Additionally, these studies aspire to develop medications with the potential of reducing progression of such conditions.

Also, we are developing imaging tools to diagnose Parkinson’s disease and related disorders early-on in the disease cycle, or even before symptoms arise. IND has developed unique protocols to provide neuroimaging in clinical trials and we have attracted research participants throughout North America to take part in our neuroimaging research studies.

Dopamine Transporter Imaging:
A tool to monitor Parkinson’s disease

Imaging Methods
Diagnosis and Disease Severity
Parkinson’s Disease Progression
Detection of Preclincial Parkinson’s Disease
Frequently Asked Questions about Imaging

During the past two decades, neurochemical brain imaging has emerged as a tool to help us understand disease process in Parkinson’s disease. Unlike an MRI or CT scan, which give us a view of the brain anatomy, neurochemical imaging uses specific radioactively labeled molecules, called ligands, as tags or markers, to show abnormalities in brain function. These tags are tools which provide a window into the abnormal dopamine nerve function in the brain in Parkinson’s disease. The radioactively labeled ligands are visualized using Positron Emission Tomography (PET) or Single Photon Emission Computerized Tomography (SPECT). These are two imaging technologies used to study brain function in Parkinson’s disease. At IND we have focused our research on the use of SPECT imaging in Parkinson’s disease. While both PET and SPECT imaging are sensitive methods of measuring brain chemistry, a major advantage of SPECT imaging in human studies is that SPECT cameras are much more widely available, making these studies simpler and less expensive to accomplish. Therefore, SPECT imaging holds the promise of and potential for an extensively accessible clinical imaging biomarker.

The strengths and limitations of functional imaging studies depend on both the imaging technology as well as the ligand or biochemical marker used to tag a specific brain neurochemical system. In our studies we have imaged the brain using a radioactively labeled marker, which binds to the dopamine transporter, a protein on the cells that produce dopamine. The specific ligand we have used in most of our studies is called [¹²³I] ß-CIT, also known as DOPASCAN.

The first question when evaluating an imaging marker is whether it reliably distinguishes individuals with Parkinson’s disease from those without Parkinson’s disease. In our studies, [¹²³I] ß-CIT and SPECT discriminated between individuals with Parkinson’s disease and healthy subjects with a sensitivity of >98%. Importantly, the pattern of loss of [¹²³I] ß-CIT activity differs in different brain regions. Specifically, in the striatum, the area of the brain most affected by Parkinson’s disease, the region of the putamen is more affected than the caudate. The caudate and putamen are two nuclear groups within the striatum area of the brain that receive input from other parts of the brain.

The aforementioned [¹²³I] ß-CIT and SPECT imaging pattern is important because it is consistent with the known changes occurring in the brain pathology from post-mortem studies. The loss of [¹²³I] ß-CIT activity is also asymmetric as expected from the asymmetry of symptoms, which occurs in most patients with Parkinson’s disease.

Therefore, [¹²³I] ß-CIT and SPECT imaging provides a biomarker both for the presence of Parkinson’s disease and for the severity of the disease process.
In clinical practice, it is most difficult to make the diagnosis of Parkinson’s disease very early in the process, at the onset of symptoms. Most patients initially develop symptoms on one side only, which is called hemi-Parkinson’s disease. In studies focused on early hemi-Parkinson’s disease, at the threshold of manifest symptoms, [¹²³I] ß-CIT and SPECT imaging demonstrated a 50% reduction in [¹²³I] ß-CIT activity in the side of the brain opposite to the symptomatic side (note that the left side of the brain controls the right side of the body and vice versa). Importantly, these data suggest that at the start of symptoms, about 50% of dopamine activity has been lost, but that potentially 50% can be protected.

A major goal of Parkinson’s disease research is to develop therapies which slow or stop disease progression and/or restore dopamine cell function. The rate of clinical progression of Parkinson’s disease is highly variable and currently unpredictable. Several clinical studies have followed large cohorts of patients with Parkinson’s disease for several years, but these studies lack an objective measure of disease progression and are frequently confounded by changes in treatment. Imaging studies provide the opportunity to evaluate patients longitudinally from early to late disease using an objective biomarker for dopamine nerve cell degeneration.

In studies evaluating sequential [¹²³I] ß-CIT and SPECT imaging in patients with Parkinson’s disease, there was an approximately 7% reduction in [¹²³I] ß-CIT and SPECT activity each year. This rate of nerve cell loss is similar to that found in another imaging study using PET and [¹⁸F]DOPA. Evidence from studies of hemi-Parkinson’s disease subjects provides further insight into the rate of progression of disease. In early hemi-Parkinson’s disease, there is a reduction in the [¹²³I] ß-CIT activity of about 50% in the brain hemisphere opposite the symptomatic side, but also a 25-30% reduction in the brain hemisphere opposite to the ‘presymptomatic’ side. Since most patients will progress clinically from unilateral to bilateral symtoms in a 3-6 year period, it is therefore likely that the loss of [¹²³I] ß-CIT activity in the brain hemisphere reflected in the previously ‘presymptomatic’ side will progress at about 5-10% per year.

Progression studies have begun to provide important new insights into the onset and natural history of Parkinson’s disease. For example, given the assumption that progression is linear, it is possible to extrapolate back in time from sequential imaging data and reported symptom duration to estimate when the dopamine neuron loss began and at what level of dopamine neuron loss symptoms began. These calculations are fraught with many assumptions, but likely provide an estimate for the duration of time between the start of the disease process and the start of disease symptoms, called the preclincial phase of the illness. Our data from longitudinal imaging studies suggest that disease symptoms start at 70-75% of normal dopamine cell function and it may take a period of 3-6 years from the start of nerve degeneration to the onset of symptoms. While the data available to calculate the estimates of the preclinical phase must be viewed as preliminary, they are consistent with other imaging studies and with pathology studies. If correct, this has tremendous implications for understanding the cause of Parkinson’s disease and for developing strategies for disease screening and treatment. For example, if preclinical disease is relatively short, repetitive screening might be required to identify affected individuals in an ‘at risk’ population. Furthermore, as potential preventative or restorative therapies are developed, these treatments might be directed to the time period from onset of degeneration to onset of symptoms.

Imaging studies also provide an objective tool to assess potential neuroprotective and neurorestorative therapies for Parkinson’s disease. Prior studies of potential neuroprotective agents have been flawed due to lack of a biomarker of progression and to reliance on clinical measures of disease.

Perhaps the ultimate goal of imaging studies is to enable us to identify reliably those people with Parkinson’s disease during the pre-clinical phase of their disease, that is, prior to the development of symptoms. While no clearly effective treatment to prevent Parkinson’s disease currently exists, these imaging studies would prepare us to use one or more neuroprotective therapies as they are developed. The most extensive preclinical [¹²³I] ß-CIT and SPECT imaging data are from studies of patients with hemi-Parkinson’s disease showing a significant reduction in [¹²³I] ß-CIT activity of 25-30% in the ‘presymptomatic’ striatum in these patients who are known to progress to bilateral disease.

If it is possible to identify preclinical Parkinson’s disease, an important practical issue is: in whom do we check? Clearly imaging studies cannot be used to screen populations because of cost and practical considerations. Therefore, a number of studies are attempting to define what makes someone ‘at risk’ for Parkinson’s disease. Certainly in a few families it appears that a Parkinson’s disease gene or genes may be important. In a study funded by a National Parkinson’s Foundation research grant our group is collaborating with Dr. Larry Golbe to image unaffected family members of large kindreds with familial Parkinson’s disease. However, the importance of genetics in most cases of Parkinson’s disease remains unclear.

What is the purpose of functional brain imaging?
Parkinson’s disease is caused by a loss of dopamine neurons in an area of the brain called the substantia nigra. The diagnosis of Parkinson’s disease can be difficult to make, especially in its early stages.

[¹²³I] ß-CIT-SPECT imaging allows physicians to measure the number of dopamine neurons in the brain. This can be useful in confirming the diagnosis of Parkinson’s disease, as well as in distinguishing it from other disorders. By repeating this imaging technique over time, we are also able to measure the progression of disease and determine whether this may be useful in evaluating the effectiveness of medications that may slow the rate of progression of PD.

What is [¹²³I] ß-CIT?
[¹²³I] ß-CIT is a radioactively labeled drug that is injected into your vein and binds to the cells in your brain that produce dopamine. Using SPECT (Single Photon Emission Computed Tomography) imaging we are able to evaluate the number of cells available to produce dopamine.

Is the scan like having a MRI?
No, only your head rests in the opening of the scanner. Your body is completely free and not confined. It is more like a CT scan.

How much radiation will I be exposed to?
The FDA has established guidelines for the radiation exposure considered acceptable in normal adult volunteers. The exposure from SPECT imaging is within limits specified by the FDA. The amount of radiation you are exposed to is more than a chest x-ray, but less than a full body CT scan.

Are there any side effects?
Although predictions of drug side effects in any individual cannot be made with certainty, to date we have noted no significant side effects in over 1000 people injected with [¹²³I] ß-CIT.

Is there any discomfort associated with this procedure?
Aside from the placement of a needle in your vein for the purpose of injecting the drug, there is no discomfort associated with this procedure.