Author: Bill Stamey, M.D.

Aging is associated with many changes in the human brain.  We may notice, for example, that short-term memory is not as robust as we get older.  One reason for this is that the hippocampus, the area of the brain that deals with the formation of short-term memory and learning, is affected by normal aging.  The reason is complicated, but the more-or-less short version of the story has to do in part with genes.  Genes are the individual instructions for function in your genetic library, the DNA.  Your DNA contains over 20,000 genes and these may be turned on (upregulated), or turned off (downregulated).  Those on/off gene switches are often influenced by chemical messages from other cells.  Selection of which genes work is one way humans can start out as a single cell (a fertilized egg), and wind up trillions of cells in the collective that is an adult.

Every living cell in your body contains the full DNA library that makes you who and what you are.  The key is that each type of cell needs different instructions from the DNA to form and carry out basic functions that make them unique cell types of the brain, liver, skin, and so on.  Even within the brain, there are many different types of cells that make up different parts and have very different functions.  The cells of the hippocampus don’t appear or function in a way similar to the cells of the basal ganglia, for example.  And, as we age, the functions of cells change for better or worse in response to needs at the time and the dictates of our genes.

Brain cells communicate with each other at points called synapses.  Imagine a cell having many branches that connect with the branches of other cells. You have over 80 billion brain cells (neurons), and each forms up to 10,000 synapses with other neurons – though the average is probably closer to 7,000.   When you learn something, it is because you are able to form new connections between neurons through a process called synaptic plasticity.  In medicine, if something is plastic, it is able to change.  Synaptic plasticity allows a set of new connections that makes a new synaptic pathway, and through that pattern of connected neurons, you have learned something.  This new learning is stored as a memory that can be called upon again.

In the older person, synapses of the hippocampus may have trouble with one of the functions of memory formation called long-term potentiation (1).  The process is influenced by genes that control synaptic plasticity.  Those genes may be downregulated, and one culprit is thought to be a tiny chemical messenger in the tissue around the cell (2).

It turns out that in younger people there are proteins in the blood plasma that upregulate the same genes.  This might be why younger people have better memory.   

Multiple times over the last several years researchers have shown that exposing older cells to young blood can improve function (3), and even reverse age-related changes to brain cells (4) and cognitive function (5), though these studies were in mice, not humans.

Researchers at Stanford University have been on the cutting edge of this investigative work, and a paper published in April 2017 in the journal Nature (6) hypothesized that plasma from human umbilical cord blood would contain “a reservoir of such plasticity-promoting proteins.”  They showed that human cord plasma treatment revitalized the hippocampus and improved cognitive function in older mice, who were better able to learn mazes and avoid unpleasant situations.  Researchers did not just test wholesale injection of plasma however.  Over 60 compounds found in the umbilical plasma were tested, and a molecule was identified that by itself made positive changes.  TIMP2, known to be present in human cord plasma, young mouse plasma, and young mouse hippocampus, was found to increase synaptic plasticity at the level of the hippocampus in older mice, and it was shown that blocking TIMP2 prevented long-term potentiation (memory formation).

In the PLasma for Alzheimer SymptoM Amelioration Study (PLASMA) (NCT02256306), Stanford researchers next trialed intravenously-administered plasma from young donors to 18 patients with mild-moderate Alzheimer disease (AD) (7).   Participants were given one unit of plasma weekly over four weeks.  The primary endpoint was a measure of safety and tolerability.  Secondary outcome measures included changes over a nine-week period in cognitive tests, functional activities, activities of daily living, and depression.  Other lab and imaging studies were also included.  No results are posted on ClinicalTrials.gov.  However, Stanford Medicine News Center quoted investigator Dr. Sharon Sha, who noted the trial showed good tolerability, but “no significant changes in participants’ mood or their performance on tests of cognition … these kinds of changes are typically observed only in clinical trials whose durations exceed one year” (8).  Thus, larger, longer studies are needed to see if these improvements would occur.  Stage of disease may be another key factor.  Still, it is encouraging that the therapy was tolerated, and the door is open to new trials.

An ongoing study at Stanford is the The Stanford Parkinson’s Disease Plasma Study (SPDP) (NCT02968433) (9), which proposes to show that “young plasma infusions can be performed safely in patients with Parkinson’s Disease (PD).”  In the study, secondary outcomes include “behavioral and laboratory data that will support the next study that will inquire whether young plasma infusions improve or slow the progression of cognitive, mood and/or motor impairment and rate markers of the disease.”  All 15 participants will undergo neuropsychological, neuropsychiatric, and motor assessment prior to receiving infusions of one unit of young plasma, twice a week over a four week duration.  Following that period, participants will undergo reassessments.  There will be no placebo arm, or as investigators put it, “no deception will be used.”  The primary outcome measure will be an assessment of safety and adverse events.  Secondary outcome measurements will include change in motor function up to eight weeks out.  Finally, there will be a measure of potential change in cognitive ability.

If compounds in young blood are helpful in PD, the goal might be to isolate them and form new therapies.  This work in PD is in the early stages of development, though it is very helpful that so much of the groundwork has been done in mice and in Alzheimer disease.

REFERENCES

1. Burke, S. N. & Barnes, C. A. Neural plasticity in the ageing brain. Nature Rev. Neurosci. 7. 2006;30–40
2. Lee, et al. Gene-expression profile of the ageing brain in mice. Nature Genet.2000;25:294–297
3. Conboy, et al. Rejuvenation of aged progenitor cells by exposure to a young systemic environment. Nature.2005;433:760–764
4. Katsimpardi, et al. Vascular and neurogenic rejuvenation of the aging mouse brain by young systemic factors. Science. 2014;344:630–634
5. Villeda, S. A. et al. Young blood reverses age-related impairments in cognitive function and synaptic plasticity in mice. Nature Med. 2014;20:659–663
6. Castellano, et al. Human umbilical cord plasma proteins revitalize hippocampal function in aged mice. Nature 2017; 544:488–492
7. https://clinicaltrials.gov/ct2/show/NCT02256306?term=NCT02256306&rank=1
8. https://med.stanford.edu/news/all-news/2017/11/clinical-trial-finds-blood-plasma-infusions-for-alzheimers-safe.html 
9. https://clinicaltrials.gov/ct2/show/NCT02968433?term=nct02968433&rank=1

In the fall, 2017 issue of MPDN we discussed focused ultrasound (FUS) (1), a specialized technique that was FDA approved to treat essential tremor (ET) in 2016.  Parkinson disease (PD) tremor is not yet an FDA approved indication, but it seems likely that it will be in the future.  Also mentioned in the MPDN article was a study of patients with PD who were given FUS.  As that study was ongoing, no data was then available. That study is now complete and has been published in JAMA Neurology as discussed below, along with two other new scientific reports.  Here we review the topic and briefly discuss the new findings and considerations.

FUS

Patients undergoing FUS experience a noninvasive MRI-guided procedure in which beams of acoustic energy (sound waves) are directed toward the same target in the brain from 1,024 tiny transducers worn around the head in a stereotactic frame.  This energy combines on the target to generate friction and heat, which destroy the target.  One could imagine an unwanted electrical signal being stopped in this way.   There are a variety of potential targets in the brain.

VIM

For ET and most reported cases of PD, the target is the ventral intermediate nucleus (VIM) of the thalamus (a deep gray matter structure present on both sides of the brain).   VIM in some ways functions as a relay for the signal which causes tremor and has been a target for deep brain stimulation (DBS), cautery, and gamma knife approaches to tremor.   As with most parts of the brain, each side governs the opposite side of the body.   FUS of the VIM is meant to cause a lesion which will stop or reduce tremor.  As this heating up is taking place it is monitored by magnetic resonance thermometry.  In other words, researchers are able to watch the lesion occur because the patient is inside of an MRI at that time. This provides confirmation that the correct target is being destroyed.  There are multiple other parts of the thalamus nearby involving among other functions such as bodily sensation, hearing, and vision.  And, there are neighboring structures involved in muscular strength, muscle tone, and balance.  As of yet, with ET only one side of the brain is treated by FUS (under FDA approval).  And, studies with PD have used FUS on only one side, which limits the risk of adverse events (AE) with the procedure.   The most common AEs with VIM FUS are numbness on the side of the body tremor is being controlled and ataxia (the loss of coordination or control of bodily movements not due to weakness).  With VIM FUS the goal is to control severe, medication-refractory tremor.

We previously referenced a small study which included 9 patients with Parkinson disease (2) with VIM FUS.   In that study, the motor score (part III of the Unified Parkinson’s Disease Rating Scale, UPDRSIII) improved from 24.9 ± 8.0 to 16.4 ± 11 at one month, and 13.4 ± 9.2 at six months after treatment, a positive result (footnote).

A recently published study took place at two different academic centers (University of Virginia Health Sciences Center in Charlottesville, Virginia, and Swedish Neuroscience Institute, Seattle Washington), and sought to answer the questions as to how safe and efficacious FUS thalamotomy (VIM FUS) is for managing medically refractory, tremor-dominant PD (TDPD), and to ask the magnitude of the placebo response (3).   Researchers identified TDPD patients from the database, and included patients whose disease was medication-refractory, severe, and disabling.  Twenty-seven patients were randomized: 20 to FUS thalamotomy, and 7 to sham procedure.   Twenty-six of the patients were male (96%), average age 67.8 years.   The group receiving the sham procedure was offered open-label treatment after unblinding.  Patients undergoing the study protocol were prepared by having their heads shaved and a stereotactic frame placed on their heads for MRI stereotactic planning.  This meant that patients would each be placed in the MRI to localize the exact target before beginning the ultrasound treatment.   Before beginning therapy, the treatment team was informed of whether each patient was to receive the sham or FUS. Ultrasound was administered with increasing energy and patients were clinically monitored after each sonication.  Tremor was assessed at rest, posture, finger to nose, and drawing.  Researchers noted that tremor did not tend to decrease until temperatures exceeded 50°C (122°F).  The stated goal during the treatment was to reach tremor suppression “at an adequate thermal dose to the target.” During the treatment headache occurred in 65% and dizziness/vertigo and 42%.  All of this resolved with completion of the procedure.  Two patients had mild persistent hemiparesis (weakness on one side of the body) with gradual improvement.  One patient had persistent mild ataxia.  Patients returned for an MRI the next day and were then discharged from the hospital.  Assessments of tremor were performed at one and three months.   Neither the patient nor the evaluators were un-blinded until the 12 month assessment.  Hand tremor was measured using a clinical rating scale for tremor (CRST) and revealed improvements of 62%, and was still present at the 12 month assessment.  The more familiar UPDRSIII (motor subsection) revealed an overall 8 point benefit (from a baseline average of 23 points) , with 1.5 point improvement of resting tremor (from a baseline average of 4 points) and 1 point for postural tremor (from baseline average of 4 points). Three patients had inadequate improvement or even mild worsening of tremor scores.  Sham treatment did not result in benefit.  Six sham patients did go on to have the full treatment after unblinding.  The most common thalamotomy related adverse events were finger tingling (39%), ataxia (35%), facial tingling (27%).  At one year tingling persisted in 19% of patients and ataxia in 4%.

VOP

A single case report from a 73 year-old Japanese patient with refractory right-sided tremor (4).  The patient could not tolerate higher doses of levodopa or dopamine agonists due to hallucinations and excessive daytime sleepiness.  He was given FUS to ablate both the VIM and the ventro oralis posterior (VOP) nuclei of the thalamus (4).  By including the VOP, investigators hoped to improve muscular rigidity (increased tone).  Right-side resting tremor and rigidity were “abolished immediately following 10 sonications with an average maximum sonication time of 13.0 ± 3.4 seconds (range 10-17 seconds).”  Temperatures inside of the thalamus reached a maximum of 60°C (140°F).  No adverse events occurred during sonications.  However, bradykinesia (slowness of movement) was exacerbated after thalamotomy and was reportedly due to local swelling of brain tissue.  The patient was given steroids and the bradykinesia resolved after two weeks.

STN

Another target to consider is the subthalamic nucleus (STN). This is the more common site used for DBS in PD because of several factors, including the benefit that not only tremor, but bradykinesia (slowness of movement) and rigidity might be improved.

An open-label pilot study (not blinded, patients knew they were getting the treatment) was done at CINAC (Centro Integral de Neurociencias), UniversityHospital HM Puerta del Sur in Madrid, Spain (5).   Ten PD patients with markedly asymmetric parkinsonism poorly controlled with medications were included.   FUS subthalamotomy was targeted with several sonications above 55°C and adjusted according to clinical response.  Total number of sonications given ranged from 17-31, though the average number of sonications above 55°C was 9.  Time spent receiving sonication ranged from 144-337 seconds.   There were pauses between sonications, and thus time spent from first sonication to completion ranged from 83-174 minutes, thus the longest time under therapy was just under 3 hours.  The goal was to safely change the motor status of the treated side of the body in both off-medication and on-medication states at 6 months.

By the 6 month follow-up, 38 non-serious AEs had been recorded, though only 7 were still present.  Three AEs were directly related to subthalamotomy: off-medication dyskinesia, on-medication dyskinesia, and subjective speech disturbance.  Four of the adverse events present at 6 months were related to medical management, and included anxiety, fatigue, and weight gain.  The most frequent AEs were transient gait ataxia (6 patients), transient head pain related to the head frame (6 patients), and transient high blood pressure during the procedure (5 patients).   During the procedure back pain was reported, likely due to position in the MRI (2 patients), “warm cranial sensations (2 patients), and nausea (4 patients).  Transient facial asymmetry (1 patient) and moderate impulsivity (2 patients) were also noted.  At six months the average motor score in the treated side of the body improved by 53% in the off-medication state and 47% in the on-medication state.

Gpi

Globus pallidus interna is a target for DBS leads.  Surgical lesions of the GPi have been shown to improve tremor, bradykinesia, rigidity, and dyskinesias.  As yet there do not appear to be any published cases regarding Gpi FUS.  However, a trial is recruiting (NCT02003248) in Seoul, Korea to study safety and effectiveness of Gpi FUS in the treatment of dyskinesia (6).  Another trial (NCT03319485) with locations in Maryland, New York, and Ohio is also recruiting to evaluate the safety and efficacy of unilateral focused ultrasound pallidotomy in the management of dyskinesia or motor fluctuations for medication refractory, advanced PD (7).   A third trial (NCT02263885) is active, not recruiting, in multiple U.S. sites including California, Maryland, Massachusetts, Ohio, and Virgina (8).   This study is designed to evaluate the safety, and initial efficacy of unilateral lesion in the globus pallidus as an adjunct to PD medications in medication-refractory PD.

PPN

Pedunculopontine nucleus (PPN) is an experimental target for DBS in the treatment of freezing and other gait dysfunction.  As yet no studies or articles are available approaching this target.

Footnote:  Recall that UPDRSIII is a 108 point scale which measures motor functions such as tremor, stiffness, slowness, gait, etc.

REFERENCES

1. https://mainepdnews.org/2017/09/28/how-close-are-we-to-focused-ultrasound-for-pd-in-maine/
2. Zaaroor, et al.  Magnetic resonance-guided focused ultrasound thalamotomy for tremor: a report of 30 Parkinson’s disease and essential tremor cases. J Neurosurg. 2017 Feb 24:1-9.
3. Bond, et al.   Safety and efficacy of focused ultrasound thalamotomy  for patients with medication-refractory, tremor-dominant Parkinson disease.  A randomized clinical trial.  JAMA Neurol.   2017;74 (12): 1412-1418.
4. Ito, et al. Magnetic Resonance Imaging-guided Focused Ultrasound Thalamotomy for Parkinson’s Disease: A Case Report.Intern Med. 2017 Dec 21. .9586-17.
5. Martínez-Fernández, et al.  Focused ultrasound subthalamotomy in patients with asymmetric Parkinson’s disease: a pilot study. Lancet Neurol 2018; 17: 54–63
6. https://clinicaltrials.gov/ct2/show/NCT02003248?term=focused+ultrasound&cond=Parkinson+Disease&rank=2
7. https://clinicaltrials.gov/ct2/show/NCT03319485?term=focused+ultrasound&cond=Parkinson+Disease&rank=9
8. https://clinicaltrials.gov/ct2/show/NCT02263885?term=focused+ultrasound&cond=Parkinson+Disease&rank=10

Delayed gastric emptying (GE) affects over 70% of PD patients (1, 2).  In other words, food or medicines may take longer than normal to leave the stomach.  This may be a problem on many fronts.  First, there is the discomfort of a stomach that does not empty.  There is the issue of early satiety, or loss of appetite, too soon in the meal.  This may mean a person is not getting enough calories.  Additionally, there is the effect on absorption of nutrients and medications, which may be impaired for several reasons.  The stomach and the intestines have very specialized jobs to do, and these may be sidelined by slow emptying.  In the case of levodopa, absorption takes place just after leaving the stomach and entering the first part of the small intestine.  Delay of GE is associated with poor absorption of levodopa and subsequent delayed ON time (the time medications are working and symptoms are controlled), and worsening motor fluctuations (for example, unexpected medication failures such as doses that do not work at all, or suddenly stop working before they should) (3, 4).

For years, researchers have attempted to deal with the problem of GE.  In the 1990s, investigators showed that cisapride (Propulsid), a prescription drug FDA approved for severe nighttime heartburn in patients with gastroesophageal reflux disease (GERD), was associated with fewer motor fluctuations in PD (5-7).  The implication was that earlier emptying of stomach contents would improve drug absorption, and therefore function, in PD patients.  However, Janssen Pharmaceuticals Inc., made a voluntary action to withdraw the drug from the U.S. market after noting that as of December 31, 1999, use of cisapride had been associated with 341 reports of heart rhythm abnormalities, including 80 reports of death.  Per the press release, most of these adverse events occurred in patients who were taking other medications, or suffering from underlying conditions known to increase risk of cardiac arrhythmia associated with cisapride (8).

The problem is that there are not many drugs available to help GE.  In the U.S., the drug metoclopramide (Reglan) improves GE, but is also a very potent dopamine receptor blocker which can exacerbate symptoms of PD, and is generally not used in this population for that reason.  To be clear, metoclopramide is possibly the most common cause of drug-induced parkinsonism in the U.S., even among those who do not have underlying PD.

Outside of the U.S., domperidone is used, and generally does not alter PD motor symptoms because it affects serotonin, rather than dopamine, receptors.  Movement disorder and gastroenterology specialists in the U.S. still frequently prescribe the drug.  However, because there is no FDA approval, it is not covered by Medicare and patients must pay out of pocket.  Most of the time the drug is obtained by patients from Canada, though compounding pharmacists may also fill capsules in the U.S., and that is likely a more expensive option.   Interestingly, use of domperidone is associated with increases in plasma levodopa concentration among PD patients (9).

What is approved in the U.S.?  Erythromycin, an antibiotic FDA approved to treat infection, has long been known to assist in gastric motility and GE.  However, there are side effect and adverse event concerns, such as the development of bacterial resistance to antibiotics, and kidney and ototoxicity.  Erythromycin has been reported in some patients to cause severe and permanent damage to the inner ear, resulting in hearing loss, deafness, and severe vertigo.  The drug was trialed NCT02005029 (10) at Virginia Commonwealth University Parkinson’s Center, Richmond, Virginia, and results were posted online at ClinicalTrials.gov in February 2017, though it does not appear the data was published in a medical journal.  The study included 4 participants who received a single dose of erythromycin and 4 who received placebo.   There was a modest improvement of GE in the erythromycin group (105 minutes) versus placebo (180 minutes).  Also reported was a small increase in plasma levodopa concentration.  The drug is used off-label by some physicians and obviously requires monitoring of side effects.

There may be a better mechanism on the horizon.  In February 2018, international researchers in the United Kingdom, Europe, and Australia published a study in the journal Movement Disorders which tested another agent, camicinal (GSK962040), a “gastroprokinetic” drug (11).

Camicinal improves GE by binding to motilin receptors in the gut.  The primary outcome of the study was to evaluate the effect of camicinal on levodopa pharmacokinetics (the movement of drugs within the body) in PD patients.  The study was multicenter (11 sites).  Participants had PD with suboptimal control of motor function while taking levodopa.  Motor fluctuations were defined in the study as wearing off, peak-dose dyskinesia, and delayed or absent ON periods that impacted functional status or quality of life.  Patients had to have a stable levodopa dosing regimen for at least four weeks prior to screening, and therapy could not be altered during the study.  Participants further had to have a delayed GE of 70 or more minutes.

Nineteen patients who had been randomized to placebo, and 37 patients to caminical 50 mg once daily, completed the study.  This was a double-blinded investigation (patients and raters were blinded to whom was receiving placebo or study drug).  Patients were treated from seven to nine days, and there was a 14-day follow up period.  GE improved by an average of 5.3 minutes in the treatment group.  Though this seems modest, there were other measures which indicated improvement, and the trend toward improvement at the end of the study would seem to indicate that a longer duration trial would be in order.  For example, by the eighth day of the study the time for maximum level of levodopa in the plasma was 23 minutes sooner with camicinal than placebo.  And, MDS-UPDRS III scores (measures of motor function in PD) improved an average of 9 points by the eighth day.  With camincinal, there was a nearly two hour improvement in ON time.

This study was the first to describe the motilin receptor agonist camicinal motor response to levodopa in PD patients with motor fluctuations.

REFERENCES

1. Cloud, et al.  Gastrointestinal features of Parkinson’s disease.  Curr Neurol Neursci Rep. 2011;11:379-384.
2. Heetun, et al.Gastroparesis and Parkinson’s disease: a systematic review. Parkinsonism Relat Disord 2012;18:433-440.
3. Doi, et al.  Plasma levodopa peak delay and impaired gastric emptying in Parkinson’s disease.  J Neurol Sci 2012;319:86-88.
4. Muller, et al.  Impact of gastric emptying on levodopa pharmacokinetics in Parkinson disease patients.  Clin Neuropharmacol 2006;29:61-67.
5. Djadldetti, et al.  Effect of cisapride on response fluctuations in Parkinson’s disease.  Mov Disord 1995;10:81-84.
6. Cisapride was shown to improve plasma levodopa levels and therefore the motor function in patients with PD.
7. Neira, et al.  the effects of cisapride on plasma L-DOPA levels and clinical response in Parkinson’s disease.  Mov Disord. 1995;10-66-70.
8. https://www.fda.gov/ohrms/dockets/ac/00/backgrd/3634b1a_tab4a.htm
9. Nishikawa, et al. Coadministration of domperidone increases plasma levodopa concentration in patients with Parkinson’s disease.  Clin Neuropharmacol 2012;35:182-184.
10. https://clinicaltrials.gov/ct2/show/NCT02005029?term=erythromycin&cond=Parkinson+Disease&rank=1
11. Marrinan, et al.  A randomized, double-blind, placebo-controlled trial of carmicinal in Parkinson’s disease.  Movement Disord. 2018;33(2):329-332.