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[00:00:23] Prof. Marjan Jahanshahi: Thank you for inviting me to participate in this podcast.
[00:00:27] Dr. Michele Matarazzo: You are the last author of an article recently published in the Movement disorders Clinical Practice titled, "Deep Brain Stimulation of the Nucleus Basalis of Meynert for Parkinson's Disease Dementia: A 36-Month Follow Up Study." So, Parkinson's disease dementia is a very significant issue for our patients as cognitive problems have a devastating Impact on the quality of life of people with Parkinson's disease.
Let me start by asking how frequent this problem is, and what therapeutic options do we have right now?
[00:00:57] Prof. Marjan Jahanshahi: Worldwide, about 10 million [00:01:00] people live with Parkinson's Disease and with the aging population across the world, this number is estimated to increase to about 17 and a half million people globally by 2040. So people now talk about a global Parkinson's disease pandemic.
And given that, within 10 to 20 years of illness, about 70 to 80% of people with Parkinson's disease develop dementia, one could also talk about the looming pandemic of Parkinson's dementia.
Parkinson's dementia has a negative impact on most domains of cognitive function, and it carries, as you said, a significant burden and cost as it increases mortality and also results in progressive cognitive and functional disability in [00:02:00] daily life and is also commonly associated with psychiatric symptoms, such as visual hallucinations and apathy, which can also be disabling in their own right. Parkinson's dementia has a negative effect on the quality of life of the patient, as well as the carer. And it results in significant carer burden and distress. And ultimately, nursing home placement of patients, which increases the cost of care.
So Parkinson's dementia is a considerable and sizeable problem. The most common medical treatment for Parkinson's dementia is with acetylcholinesterase inhibitors, which clinical trials have shown to be of mild to moderate benefit for the cognitive symptoms of Parkinson's dementia.
And because of this, it's been [00:03:00] considered important and perhaps timely to explore other treatment options for Parkinson's dementia.
[00:03:07] Dr. Michele Matarazzo: Great. So as you just mentioned, the only therapeutic option is the acetylcholinesterase inhibitors. But you decided in your study to opt for a more invasive approach using deep brain simulation.
So first of all, why did you choose nucleus basalis of Meynert as a target?
[00:03:25] Prof. Marjan Jahanshahi: Parkinson's dementia is considered the Lewy body dementia. But the pathological processes underlying Parkinson's dementia are not restricted to cortical lewy bodies, but more complex. And most importantly, there is now convincing evidence from earlier studies and more recent studies that there is up to 70% degeneration of the nucleus basalis of Meynert, which is associated with cognitive impairment and dementia in Parkinson's [00:04:00] disease.
So the nucleus basalis of Meynert or the MBM, as I will refer to it for short from now on, is an important area of the brain in relation to Parkinson's dementia. The MBM is the main source of acetylcholine projections to the cortex. And animal studies have shown that the MBM is involved in sleep-wake regulation in arousal, in alertness, attention and memory. And stimulation of the MBM in rodents increases cortical acetylcholine release and promotes a wakeful and alert state, whereas conversely, lesions to the MBM result in a reduction of alertness or a comatose state. And preclinical studies have established that deep brain stimulation of the MBM improves cognitive performance on a [00:05:00] range of tasks such as working memory in a Primate study.
So In light of the success of deep brain stimulation of the subthalamic nucleus and the internal segment of globus pallidus for the control of the motor symptoms of Parkinson's disease the potential of deep brain stimulation for Parkinson's disease dementia has also been explored. Given that presence of dementia had been an exclusion criterion for deep brain stimulation for the motor symptoms of Parkinson's disease, a primary question has been whether deep brain stimulation is in fact safe and well tolerated in people with Parkinson's dementia. And in terms of choice of target for deep brain stimulation in Parkinson's dementia, up to now, the MBM has been the main target for the reasons that I just explained.[00:06:00] And in 2009, Freund and his colleagues reported a single case study of a 71-year-old man who had Parkinson's dementia, who had deep brain stimulation of the subthalamic nucleus, and also by bilateral deep brain stimulation of the MBM.
The subthalamic stimulation improved the motor symptoms and the speed of processing on tasks such as the train making test, but didn't influence performance on other cognitive tests, whereas switching the MBM stimulators on improved episodic memory and also improved the patient's drive and communication and also apraxia.
And these improvements were reversed when the MBM simulators were switched off. So these were the reasons for our selection of MBM as [00:07:00] a target for deep brain simulation in Parkinson's dementia.
[00:07:05] Dr. Michele Matarazzo: Great. And what outcome did you expect from the trial?
[00:07:09] Prof. Marjan Jahanshahi: So the Freund single case study was open label and the STN DBS and the MBM deep brain stimulation may have produced synergistic effects in this single case. Following this single case of showing symptomatic benefit in Parkinson's disease dementia, our group at UCL Queen Square Institute of Neurology, we obtained ethics approval and completed the randomized double blind ham-controlled cross-over trial of bilateral MBM DBS in six male patients with Parkinson's disease dementia. And I don't have time to go into the details, but the most ventral contacts of the electrodes were placed in the CH4 intermediate [00:08:00] section of the MBM, which is the largest section with cortical and parahippocampal projections. And stimulation was delivered bilaterally at 20 hertz with a pulse suite of 60 microseconds and The double blind crossover phase 1.5 or three volts to which the patients were randomly assigned , and alternated six weeks of MBM DBS and six weeks of sham stimulation with a two week washout period in between. And then following these, there was an open label phase of MBM stimulation with six and 12 months follow up of the patients.
Our primary aim was to determine the safety and tolerability of MBM stimulation. And we established that [00:09:00] in carefully selected patients, deep brain stimulation of the mbm in Parkinson's, dementia is safe and well tolerated as there were no major adverse events other than the electrode cap showing through the scalp in one patient, which resulted in one electrode being removed after the 12 months follow up.
And in this study we used an abbreviated cognitive battery focusing on alertness, attention and memory — functions that are considered to be mediated by the mbm, which included the California verbal learning test, digit span verbal fluency, positive correlatory orienting of attention, and simple and choice reaction time. And we use these tests to compare the effects of MBM stimulation on versus MBM stimulation off. And when making this comparison, there was no [00:10:00] effect of stimulation on MBM stimulation on any of the primary cognitive or secondary measures of cognitive function or behavior. The only thing that changed was that visual hallucinations were improved in two cases when this MBM stimulation was on.
So despite the lack of symptomatic cognitive benefit, the primary aim of establishing the safety and tolerability of MBM stimulation in patients with Parkinson's disease dementia was fulfilled in this first study.
[00:10:39] Dr. Michele Matarazzo: Great. So the methods and the results of these clinical trials have been already published before. Can you share with us what we knew already and what are the main results of this new analysis?
[00:10:49] Prof. Marjan Jahanshahi: So the original trial of MBM stimulation in Parkinson's dementia, was published in 2017. This new analysis is[00:11:00] a 36-month follow up study of five of the six patients with Parkinson's dementia, which had just been published in Movement Disorders Clinical Practice.
We used the mini mental state examination and the dementia rating scale, which were also administered in the original study, as the cognitive outcome measures in this follow up study. And one of the original six patients had died at the time of the three-year follow up from causes unrelated to deep brain stimulation and there were three main findings from this new 36 months follow up study.
The first finding was that we showed the long-term safety and tolerability of MBM deep brain stimulation over the three years with no adverse effects documented in the three year period.
The second main finding was [00:12:00] that we found that the long term course and trajectory of dementia was dissimilar across the five cases. While three of the patients showed cognitive , over the three years, two of the five patients with Parkinson's dementia showed stable cognitive function as measured on both the minimal state examination and the dementia rating scale — suggesting relatively stable cognition and slower progression of their dementia over the three years of the MBM deep brain stimulation.
Now whether slower progression of cognitive decline in these two patients was in any way related to responsiveness to MBM stimulation really requires confirmation in a larger series that includes an un operated control [00:13:00] group of people with Parkinson's dementia. And in one of these two patients, visual hallucinations were improved, and for the other patient carer burden was also reduced.
Now the third main finding from this follow up study was that the two patients who had more stable cognition over the three year follow up had less daytime sleepiness and higher accuracy on the Posner covert orienting of attention tests at baseline prior to surgery. This potentially identifies these two measures, daytime sleepiness and covert orienting of attention, at baseline as markers for relatively preserved acetylcholine in the mbm.
And for selection of patients who would be more likely to benefit from simulation of the MBM for [00:14:00] Parkinson's dementia in the long term.
[00:14:02] Dr. Michele Matarazzo: If you had the possibility to redesign the clinical trial with what you have learned, would you change anything? And what would be the next steps to keep unraveling the potential of DBS for people suffering from Parkinson's disease dementia.
[00:14:15] Prof. Marjan Jahanshahi: I think in future trials of MBM stimulation for Parkinson's dementia, a number of changes could be made. First, I think the inclusion criteria could be refined or expanded to include measures such as less daytime sleepiness and higher accuracy on covert orienting of attention tasks, because our results suggests that there are individual differences in response to MBM stimulation based on these measures at baseline. Other studies in Alzheimer's disease by Kuhn and colleagues have also suggested such [00:15:00] individual differences, and that younger patients with less severe dementia baseline benefit more from MBM stimulation. So refining patient selection criteria, I think, is important in future studies.
The second thing would be maybe to determine the optimal stimulation parameters. Up to now, 20 hertz deep brain stimulation has been used as this is the sort of physiological discharge rate of MBM neurons in animals and shown to stimulate acetylcholine release from cortical terminals in animal studies. So all studies to date have used continuous MBM stimulation, but there is a primate study by Liu and colleagues, which suggests that while continuous stimulation of the mbm may have inhibitory [00:16:00] effects, intermittent Stimulation of the mbm — for example, with stimulation being on for 20 seconds and off for 40 seconds — may be more effective in improving working memory in the primates. So such intermittent MBM stimulation needs to be explored in future studies.
And the other possibility is to explore the effects of deep brain stimulation in other sub region of the nucleus basalis of Meynert. Most studies have stimulated the CH4 intermediate section of the MBM, as this is the largest section. But perhaps other section of the mbm, which show less degeneration in Parkinson's dementia, could be used as a target in future studies.
And the other important change would be the inclusion of an [00:17:00] unoperated control group in future studies, including non-operated or non stimulated or delayed stimulation control group of people with Parkinson's dementia, I think is essential.
In this three year follow up study, we compared the annual rate of decline in our patients to other published longitudinal studies of Parkinson's dementia. But this is not ideal and can be problematic as differences in dementia severity and demographic characteristics across studies can be confounding factors. So including an control group, I think is essential.
The fifth thing could be including long-term follow up, I think is also essential, as there are maybe changes in brain plasticity and delayed clinical benefits may become evident as [00:18:00] shown by our three year follow-up study.
And finally, there is some evidence from animal studies that MBM stimulation releases acetylcholine in cortical areas. But using molecular imaging to investigate acetylcholine release in future clinical studies with MBM stimulation would also be important. There could also be the use of MRI to examine the effects of MBM simulation on the various networks such as the default mode network, the executive network, the salience network, all of which are deficient in dementia, to see whether there's any change in connectivity of these networks with stimulation.
[00:18:51] Dr. Michele Matarazzo: Well, you raise a lot of very good points and it seems that there is a lot of work to do still to understand what will be the role of deep brain simulation for people with [00:19:00] Parkinson's disease dementia. So, hopefully we'll see all of these questions answered in the future.
Is there anything else that you would like to share with our listeners?
[00:19:09] Prof. Marjan Jahanshahi: I think we are in the early stages of development of deep brain stimulation for dementia, and this is likely to be developed further and refined in coming years. Similar to the advances that have been made over the past decades in deep brain stimulation for treatment of the motor symptoms of Parkinson's disease.
I would like to thank you for this opportunity to talk about our studies, which were obviously completed through a team effort. The original two trials of MBM stimulation in Parkinson's dementia, and dementia of Lewy Body Disease and associated local field potential and MEG studies were part of the PhD of James Gratwicke, a young [00:20:00] neurology fellow who was supervised by Tom Foltynie and myself. And the three year follow up study was completed by Davide Cappon, an Italian psychologist from the University of Padova, worked in my group for a year. I would also like to acknowledge the contributions of the neurosurgical and nursing colleagues at the unit of functional neurosurgery at the UCL Queen Square Institute of Neurology and the National Hospital for Neurology and Neurosurgery.
[00:20:32] Dr. Michele Matarazzo: Well, thank you very much for your time, and thank you also for acknowledging the team effort, which I think it's very important to remember this when we talk about research, it's 99% of time a team effort. And all of the parts are really crucial for advancing in the understanding of Parkinson's disease and everything in research.
So thank you very much. It has been a pleasure to have you on the MDS podcast.
[00:20:56] Prof. Marjan Jahanshahi: Thank you. It's been a pleasure to talk to you.[00:21:00]
[00:21:00] Dr. Michele Matarazzo: We have had Professor Marjan Jahanshahi, and we have discussed the article, "Deep Brain Simulation of the Nucleus Basalis of Meynert for Parkinson's Disease Dementia: A 36- Months Follow Up Study," from the Movement Disorders Clinical Practice. Don't forget to download and read the article from the website of the journal.