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Does Deep Brain Stimulation (DBS) prevent progression of Parkinson’s Disease (PD) or it only masks some of the symptoms of PD?

Oleg Kopyov MD PhD Principal Investigator (St John's Oxnard), Brian Ross MD PhD Principal Investigator (HMRI), Alexander Lin MS Neuroscientist (HMRI and RSRI), Thao T. Tran BS MR spectroscopist (HMRI and RSRI), William Theurer MD Neuroradiologist (St J

Long term biochemical changes in the Parkinsonian brain with and without deep brain stimulation using Magnetic Resonance Spectroscopy (MRS).

Sub-title:  Non-invasive Neurochemical Monitoring of Parkinson’s Patients undergoing DBS is being performed at St. John’s Hospital, Oxnard, California and Huntington Medical Research Institutes, Pasadena, California, in a bid to discover whether DBS goes further than controlling symptoms (tremor and rigidity are significantly improved by this neurosurgical approach) by preventing cognitive deficits.

 A proportion of PD patients develop cognitive deficits as they age (so called Lewy Body Dementia (LBD).  Using a revolutionary brain imaging method, magnetic resonance spectroscopy (MRS) we observed neurochemical changes of LBD in four of 19 PD patients (20%) on medical treatment alone.  With the hypothesis that DBS may prevent progression of PD, we are now examining these patients again after treatment, in anticipation that DBS may prevent the development of these troubling cognitive defects.

During the last decade deep brain stimulation (DBS) has become a widely accepted method for the treatment of advanced Parkinson’s disease (PD).

However, little is known about the mechanisms of DBS for the subthalamic nucleus (DBS-STN) action. Protection of brain cells (neuroprotection) has been theorized to occur by eliminating STN-mediated excitotoxicity in animal models of PD. What that means is that PD makes the STN hyperactive. This hyperactivity results in production of excessive amount of glutamate – a chemical that normally excites the brain cells – neurons. Too much of glutamate overexcites (overworks) the cells. If this condition lasts, eventually the overworked cells die – the phenomenon known as glutamate toxicity.

It is quite logical to assume that if DBS turns off the STN, the glutamate toxicity also disappears, that is the neurons are not been killed anymore. It has been shown in animals already that destruction of the STN in animals with a model of PD prevents death of neurons in yet another structure of the brain called striatum.

The important question is whether protective role of DBS-STN takes place when we perform it in the patients with PD? It is very well known that a lot of things we are finding in animal models are not relevant to human diseases.

Magnetic Resonance Spectroscopy (MRS) can help us to answer this question. MRS looks and feels exactly as a routine Magnetic Resonance Image (MRI), but a different software transforms MRI into MRS – a highly sensitive, totally noninvasive (no injections at all), and quantitative tool that will contribute to studying mechanisms of PD and DBS. MRS can assist in diagnosis of Alzheimer’s disease (even when there are no clinical symptoms yet) and PD and differentiate between them. MRS will help to better understand the progressive nature of PD and, thereby, to fight it at the earlier stages. It will help to reconsider the timing of DBS: should it be performed only at a very advanced stage of PD as the last line of defense, or somewhat earlier?

Using the enormous investigational potential of MRS, The California Neuroscience Institute in collaboration with Huntington Research Institutes, has launched a longitudinal study ‘Does DBS-STN retard progression of PD?

The project will involve 24 patients with DBS and 24 patients without DBS. The latter group will help us to better understand the natural progression of  PD, determine which areas of the Parkinsonian brain undergo progressive degeneration, and serve as the control for the patients with DBS.

Possible outcomes:

1)    Using MRS we prove that DBS protects brain from progressive degeneration.

2)     DBS-STN only masks the PD symptoms and does not address the disease itself.

3)    Better understanding of the progressive nature of PD.

Our open label pilot 2 year long MRS study has shown in two PD patients that DBS-STN has mitigated or reversed neuronal loss in the basal ganglia of the brain.

Results:

1.     We have established the first PD MRS data repository to transfer MRI and MRS data acquired in PD patients to a central database where raw data is analyzed and quantified.  This ensures that data processing routines are normalized and quality control is maintained, both of which are critical to the success of MRS in the presence of deep brain stimulators.  Over 100 spectra from patients and control subjects have now been acquired in this ongoing clinical trial, using non-invasive MRI and MRS monitoring, supervised by Alexander Lin and Thao Tran at HMRI.

2.     We have reached the first goal of establishing a non-invasive neurochemical test using MRS to screen patients for evidence of Lewy Body dementia.  Using NAA/Cr and mI/Cr measurements from normal controls in conjunction with previously acquired data in patients with known dementia, a neurochemical screen can be established using the two measurements as shown in Figure 1.  Patients with dementia (open square) show decreased NAA (loss of healthy neurons) and increased mI (increased glial activity) when compared to normal controls (filled square) which can be used to establish a receiver operator characteristic (ROC) as shown by the dotted line.  The PD patients (indicated by X) can therefore be screened using this ROC.  Our results demonstrate that four of the 15 PD patients show evidence of dementia.

Conclusion:

We have successfully established much of the groundwork for this research project:

1)    electronic data transfer of the MRS data acquired at St. John’s not only allows for quantitative measurements and databasing of all data but also provides quality control.

2)    A significant amount of control data has been obtained in both normal healthy age-matched subjects as well as those with Parkinson’s disease but without DBS treatment.  These datasets are important for establishing statistical validity.  The results demonstrate excellent reproducibility and sensitivity of MRS for treatment monitoring.



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