CME: New Treatments for Parkinson’s Disease

Explore cutting-edge Parkinson's treatments! Review advanced DBS, gene, and stem cell therapies, and new drug delivery methods in this FREE online CME.

Read Article, Take Test, Get FREE 🎓CME Certificate with Valid Email

We’ll send you occasional updates. Your email stays private—never sold or shared. 😇

By Stuart M. Caplen, MD 

Parkinson’s disease (PD) is an incurable neurodegenerative disorder that may present with bradykinesia, resting tremor, rigidity, postural instability, subtle motor features, and/or many non-motor symptoms.  A PD presentation can be classified as tremor-dominant, rigid-akinetic (often associated with postural instability and gait disorders), or intermediate with components of both.  Non-motor symptoms of PD include constipation, depression, pain, sleep disorders, loss of smell, as well as cognitive decline, and autonomic dysfunction.[1]  Many motor symptoms in Parkinson’s disease are a result of the loss of the dopaminergic neurons in the substantia nigra pars compacta, which send axons to the striatum (consisting of the caudate, putamen, and the nucleus accumbens).

Most of the current pharmacologic therapy for PD is aimed at restoring dopaminergic tone in the striatum. The most commonly prescribed medication is levodopa, which is converted to dopamine in the brain.  It is typically combined with carbidopa (a decarboxylase inhibitor), which prevents the levodopa from breaking down before it reaches the brain.  Many symptoms of PD, such as cognitive impairment and autonomic dysfunction, mainly have a non-dopaminergic basis due to neurodegeneration at other sites in the central, enteric and autonomic nervous systems.[2]  It is estimated that there are approximately one million patients with PD in the U.S. and 90,000 new cases per year.[3]

While medications such as levodopa can improve motor functioning, there are a number of issues associated with its use. There may be variability in medication absorption and its ability to cross the blood-brain barrier. There may be side effects from delivering dopamine to extra-striatal regions of the brain, such as the non-physiological release of dopamine in the basal ganglia.  Patients with PD who are treated with levodopa can develop cognitive problems, levodopa-induced dyskinesias, and on-off fluctuations, which consist of good symptom control periods, with improved mobility and possibly an increase in levodopa-induced dyskinesias, varying with poor symptom control periods.[2]  Levodopa has a short plasma half-life of 36-96 minutes, which requires multiple doses during the day and leads to an “off” period, particularly overnight while sleeping.[4]  Because of the lack of full control of PD by medications such as levodopa, other modalities are being researched.[2]

Other Medications and Delivery Methods for PD Treatment

There are a number of medications besides levodopa that can be used to help reduce PD symptoms.

• Amantadine is an antiviral medication that may be prescribed to reduce levodopa-induced dyskinesias.  The exact mechanism by which amantadine achieves this effect is unknown.  One theory is that it causes inhibition of  N-methyl-D-aspartate (NMDA)-glutamate receptors that may correct dysregulation of glutamatergic transmission in the basal ganglia, which may be a cause of the dyskinesias.  Amantadine also appears to increase dopamine release and blocks dopamine reuptake.[4,5]

• Enzyme inhibitors reduce the activity of enzymes that break down dopamine to enhance the activity of dopamine.  Monoamine oxidase B (MAO-B) inhibitors include safinamide, selegiline, and rasagiline. Catechol-O-methyltransferase (COMT) inhibitors such as entacapone and opicapone may also be prescribed.[2,5]

• Anticholinergic medications, such as benztropine mesylate and trihexyphenidyl, block acetylcholine’s action.  Imbalances in the dopaminergic and cholinergic neurological pathways can lead to overactivity of cholinergic pathways, which can cause dyskinesia and tremors.  Anticholinergics may help reduce these symptoms.[4,5]

• Dopamine agonists, such as pramipexole, ropinirole, rotigotine, bromocriptine, and cabergoline are typically used in younger patients or in early stages of PD.  They activate dopamine receptors and may lengthen the time levodopa is effective decreasing symptoms in the levodopa “off” phase.[4,5]  Apomorphine, which was in the past used as an emetic, is also a dopamine agonist and can be administered intravenously or subcutaneously to prevent off-time symptoms in patients with more advanced PD, or in those undergoing surgical procedures.[6]   

• Cholinesterase inhibitors block the enzyme cholinesterase, which breaks down acetylcholine. Rivastigmine and donepezil are two cholinesterase inhibitors that have been in preliminary studies testing their ability to improve gait and reduce falls in PD patients.[2]

• Noradrenaline reuptake inhibitors such as methylphenidate and atomoxetine are being investigated for their effects on balance and gait in PD in an ongoing trial.

• Adenosine A2A antagonists, such as istradefylline, can help improve motor symptom control especially during levodopa “off” periods.  Adenosine is thought to block dopamine release in the basal ganglia and thus blocking adenosine may increase dopamine levels.[5]

• Levodopa gel can be administered via a percutaneous endoscopic gastrostomy tube to prevent off-time symptoms as it had been found that continuous dopaminergic stimulation may reduce dyskinesias.[6]

• A specially designed gastric-retentive oral drug delivery system containing carbidopa and levodopa in both immediate and extended-release forms was tested to try to prevent the on-off cycles of dyskinesias at high blood levels of levodopa and worsening of PD symptoms with low levodopa blood levels.  Unfortunately, a phase 3 trial showed no advantage over standard carbidopa/levodopa oral medication. [7,8]

Alpha-synuclein Inhibition

Alpha-synuclein (α-synuclein) is a protein of unknown function, found mostly in brain tissue, that is thought to be involved in normal neurotransmission.  In PD, misfolded alpha-synuclein is thought to form clumps (or aggregates) that can cause inflammation and interfere with neuron function.  These clumps of protein, primarily composed of alpha-synuclein, are known as Lewy bodies.  Lewy bodies are also found in Lewy body dementia, but in PD the Lewy bodies primarily affect dopamine-producing neurons. There are case reports of families with mutations or duplications in the gene that produces alpha-synuclein, where members have a high predisposition for PD as the mutation is passed on as an autosomal dominant gene.[2,9,10,11]

Experimentally, researchers have tried to treat PD with monoclonal antibodies to reduce serum alpha-synuclein, in the hope of reducing brain alpha-synuclein.  Prasinezumab reduced serum levels of alpha-synuclein by about 97% in phase 1 trials and further phase 2 trials are ongoing.  Another antibody trial, testing the monoclonal antibody cinpanemab, was terminated due to lack of meeting predetermined outcome measures.[2]

PD01A is an experimental vaccine which is designed to induce an active immune response against alpha-synuclein.  PD01A passed phase 1 trials and is now in phase 2 testing.  ACI-7104 is another antibody-inducing vaccine that is now in phase 2 testing.[2]  There are a number of other phase 1 trials or in recruitment for phase 2 trials for other vaccines in attempts to produce alpha-synuclein antibodies.[12]

Other approaches, such as creating anti-sense oligonucleotide or using ribonucleic acid (RNAi) interference medications to reduce alpha-synuclein are also under early investigation.[2]

There are some issues with attempting to reduce alpha-synuclein levels with vaccines. It is not established that symptoms of PD are actually caused by alpha-synuclein. It is not known how much of the antibodies produced will cross the blood-brain barrier and actually get into the brain. Since the normal function of alpha-synuclein is not fully understood, it is not clear whether suppressing production could lead to other

problems.[2] As an example, one study found that injecting small-interfering RNA targeted to alpha-synuclein into rat brains caused some problematic neurodegeneration.[13]

Medications already in use that have been found to reduce alpha-synuclein levels include terazosin, β-agonists, drugs that impair mitochondrial function such as ursodeoxycholic acid and N-acetylcysteine, anti-neuroinflammation drugs such as azathioprine and sargramostim, and exenatide, a GLP-1-receptor activator. Many of these and more compounds are currently in clinical trials.[2]

Neurotrophic factors

Putamen brain injections of neurotrophic factors, which are necessary for the growth, survival and maintenance of neurons, have been trialed.  Certain proteins such as glial cell line-derived neurotrophic factors, and cerebral dopamine neurotrophic factor, which have been shown in animal studies to protect dopaminergic neurons, have been tried in humans with mixed results.[2]

Gene Therapies

Gene therapies are being evaluated in an attempt to increase dopamine levels in the striatum through the introduction of genes that mediate dopamine synthesis.  A number of these are being tested using adeno-associated virus (AAV) or lentivirus (LV) as carriers, which are infused directly into the putamen. One advantage of gene therapy is that only one administration is needed as compared to neurotrophic factors, which require multiple injections.[2,12]

Stem Cell Therapy

In the 1980s and 1990s, fetal mesencephalic dopaminergic tissue was implanted into human putamens and some open-label studies demonstrated improvement in PD symptoms.  However, in 2001 a double-blind study that included a sham surgery arm reported that at one year there was no significant difference between groups receiving the implant and those receiving sham surgery.  15% of the patients developed dyskinesias or dystonia when not on PD medications.  The grafts were associated with improved motor function in the off-medication state in younger patients but not in patients older than 60 years, the typical age range for PD.[14]

In recent years with more advances in stem cell research, implanting dopaminergic stem cells has again become an area of interest.  In 2025, there were two published reports on phase 1/2 or phase 1 trials.  In one, seven subjects received bilateral transplants of dopaminergic stem cells derived from induced pluripotent stem cells* at varying doses.  The subjects were given the immunosuppressive drug tacrolimus for 15 months.  At one year there were no off-time graft-induced dyskinesias during “off” periods, although dyskinesias from medications during “on” periods did worsen in six of the patients.  No serious side effects were reported.  Four of the subjects showed improvement in motor function during the medication-off periods.  Subjects who received higher doses of stem cells produced more dopamine at the transplant site than those who received lower doses.  No new tumors at the transplant sites were found.[15]

The other study was a phase 1 trial with 12 participants receiving either low-dose or high-dose human embryonic stem cells* injected into the putamen.  The patients were put on immunosuppressive steroids and tacrolimus for a year to prevent rejection.  The only significant adverse side effect was a single seizure in one patient soon after the surgery.  There were no tumors or graft-induced dyskinesias.  There was also improvement in DS-UPDRS Part III scores** for levodopa off-times, with more improvement seen in the higher dose group.[16]

(*The difference between embryonic and pluripotent stem cells is that the embryonic stem cells are derived from blastocyst cells, and induced pluripotent stem cells are created from reprogramming somatic cells, such as skin cells.  Both are actually pluripotent and have the ability to differentiate into almost any type of body cell.)

(** The motor examination section of the Movement Disorder Society Unified Parkinson's Disease Rating Scale, a standardized assessment tool.)

Deep Brain Electrical Stimulation (DBS)

Before the use of levodopa in the late 1960s, PD was often treated surgically with ablation of neural pathways that seemed to improve PD symptoms.  In the 1990s, it was discovered that providing electrical impulses to those neural pathways duplicated the effects of ablation.  DBS has some advantages over ablation as no tissue is destroyed, it can be turned on and off, and the amount and type of energy used can be adjusted.  One theory that partially explains why DBS works is that the high-frequency stimulation disrupts the pathological neuronal firing pattern in the targeted brain cells.[1]

The procedure involves surgically inserting electrodes into the brain through a burr hole and then tunneling the wires to the anterior chest to a subcutaneously placed battery and controller in the upper anterior chest.  Once DBS is started, it is considered a lifelong treatment.  If the battery depletes or another technical issue acutely terminates DBS, a severe rebound of PD symptoms may occur, which may necessitate emergency medical care until the problem can be solved.  Regular battery and device monitoring is required to try to avoid these issues.[1]

Three areas of the brain that are typically targeted in DBS are the ventral intermediate nucleus of the thalamus (VIM), the globus pallidus internus (GPi), and the subthalamic nucleus (STN).  All three have various advantages and disadvantages, which will be discussed later.  DBS can be unilateral or bilateral, and is usually performed bilaterally in patients with more severe disease.  Bilateral DBS of the GPi is typically better tolerated than bilateral VIM or STN, because it carries less risk of stimulation-induced dysarthria.[1]

Genetic screening might be recommended for younger patients and those with atypical presentations of PD.  Certain familial genetic mutations that predispose to PD have been found to respond to DBS better than others.  Patients with mutation in the Parkin gene or the leucine-rich repeat kinase 2 (LRRK2) gene generally have a good long-lasting outcome from DBS, while patients with glucocerebrosidase mutations do not.[1]

There are ongoing preliminary studies of using DBS in other parts of the brain, such as the pedunculopontine nucleus, substantia nigra reticularis, and the dentato–rubro–thalamic tract to try to determine if efficacy can be improved and side effects decreased.[1,2]

Effectiveness on Symptoms by DBS Type

Ventral Intermediate Nucleus of the Thalamus DBS

Of the three approaches, VIM DBS is the most effective for tremors, however it has less of an effect than the other two commonly used brain DBS targets for rigidity, akinesia gait, and dyskinesias.  Thus, it is mainly used for patients whose main clinical issue is tremors.  Besides the risk of dysarthria, balance disturbances may also be an adverse effect due to spread of the current to the adjacent motor internal capsule.[1]

Globus Pallidus Internus DBS

GPi DBS is most commonly used to correct dopamine induced dyskinesias, which include painful dystonia, rigidity, akinesia and tremors.  It has a lesser effect on gait disturbances, such as freezing of gait. There is no age limit for use of GPi DBS and the risk of negative effects on balance and dysarthria are less than with VIM DBS.  Given its positive effect on dyskinesias, GPi DBS allows the patient to continue dopaminergic medications or even increase them if needed, without the risk of dopamine-induced dyskinesias.[1]

Subthalamic Nucleus DBS

STN DBS has a similar effect on tremors and rigidity as GPi with an added advantage of being the best of the three approaches for akinesia, gait and axial disturbances, (axial disturbances are balance, posture, speech, swallowing, locomotion, freezing of gait, and axial rigidity).  It is not as effective as GPi DBS for dyskinesias but is better than VIM DBS.  Potential issues with STN DBS include dysarthria, as well as mood swings and behavioral changes due to its proximity to the limbic cortical structures.  There is also a potential risk for eyelid opening apraxia (difficulty opening the eyelids that can be treated with botulinum injections).  Doses of dopaminergic medications, especially dopamine agonists, need to be decreased after surgery, as STN DBS will potentiate their effect, which can lead to increased impulsivity and mania.  However, if dopaminergic medications are decreased too much because of improved motor function, patients may suffer from apathy and depression.  The required adjustment of medication doses makes STN DBS somewhat more challenging to manage than GPi DBS.[1]

In preparation for implantation of an STN DBS, several tests need to be performed.  One is the levodopa challenge, where motor symptoms are quantified before and after the administration of levodopa.  The greater the improvement of symptoms after a levodopa challenge, the more likely that the patient will benefit from STN DBS.  A psychiatric evaluation of the patient should be performed to avoid using STN DBS in patients with severe or untreated depression.  In some patients, there may be cognitive decline after STN DBS, so neuropsychologic testing is also generally performed to evaluate cognitive skills, including memory and executive function.  Studies have also revealed that while older patients may attain some improvement, they do not respond to STN DBS as effectively as younger patients.[1]

To be approved for STN DBS, patients should have no or only mild cognitive impairment;  absence of, or well controlled psychiatric disease; younger age (in some centers, a cutoff age of  69-70 years has been instituted); and good response to the levodopa challenge.

There has been some research into whether administering STN DBS to younger patients with PD earlier in the course of their illness might be helpful.  The EARLYSTIM study looked at this.  Subjects with troubling on/off symptoms who underwent STN DBS a median of seven years after diagnosis had better quality-of-life and motor outcome measurements compared to those treated 11 or more years after disease diagnosis.[1,17]

In patients with dopaminergic medication-induced impulse control disorders, STN DBS may be considered instead of GPi DBS, because only STN DBS allows decreasing the dose of dopaminergic medication.[1]

DBS Side Effect Control   

Some adverse side effects of DBS may be controlled by an alteration of electrical stimulus strength, amplitude, pulse width, frequency, or polarity.[1]

Adaptive Deep Brain Stimulation ( aDBS)

In March 2025, the FDA approved a device that can deliver adaptive deep brain stimulation (aDBS).  Unlike standard DBS, aDBS adjusts stimulation parameters in real time, based on brain activity, whereas standard DBS only uses fixed parameters.  aDBS is based on measuring local field potential (LFP) in the GPi or STN. (aDBS measures LFP beta-band activity, a specific frequency range.)  LFP is thought to be a measure of synaptic input to neurons.  It has been found that the level of LFP activity decreases with PD medications and is present at higher levels in approximately 95% of patients in the off-medication state.  By delivering electrical impulses based on the patient’s LFP levels, aDBS can automatically adjust stimulation during “on” and “off” states.

By measuring and responding to brain activity, aDBS potentially may reduce medication needs, improve off-time motor symptoms, and reduce periods of dyskinesia from excessive levodopa therapy.  aDBS may be most useful in STN DBS, where DBS in combination with levodopa can lead to adverse effects.[18,19]

This technology was approved on the basis of the ADAPT-PD trial.  In that trial, 84% of the subjects had an LFP signal strong enough to use for aDBS programming.  There were two aDBS modes used in the study.  One was the single-threshold mode, with the device being set at a higher or lower level of stimulation based on the LFP signal setpoint used.  Dual threshold programming adds a middle zone, which allows for a more gradual increase and decrease of the electrical impulses.  Depending on the clinical setting, one mode may prove superior to the other.[18,19]

Some patients have already received aDBS implants in 2025.  As more of these devices are implanted, additional research and refinements to the technique are likely to follow.

Magnetic Resonance Imaging-guided Focused Ultrasound (MRgFUS)

There has also been interest in MRgFUS as an alternative to DBS.  In MRgFUS, an externally directed ultrasound beam heats and ablates brain tissue.  No anesthesia is required.  A meta-analysis and systematic review of 20 studies and 258 subjects with drug-resistant PD, reported that the motor examination section of the Movement Disorder Society's Unified Parkinson's Disease Rating Scale (MDS-UPDRS) improved for tremor and bradykinesia in MRgFUS treated patients, but over time the therapeutic effect decreased.  This decrease could represent an issue with the long-term effectiveness of MRgFUS or may be due to the progressive nature of PD.  MRgFUS had a positive impact on the treatment of motor symptoms in drug-resistant PD patients, especially in terms of tremor and bradykinesia.  There were adverse events in about 25% of subjects including: headache, ataxia, speech disorders, and dizziness.  Most adverse effects resolved within three months.  The authors concluded that more rigorous study designs, larger sample sizes, and longer follow-up times were needed to fully evaluate this modality.[20]

Spinal Cord Stimulation Therapy for Gait Dysfunction

Epidural spinal cord stimulation has been used to relieve chronic neuropathic back pain in patients.  There has been some research looking at this modality to alleviate motor and gait disorders in PD.  Authors of a comprehensive review looked at 27 case reports and studies.  The mechanism of action of epidural spinal cord stimulation for PD is not known, but one theory is that it disrupts aberrant low-frequency synchronous oscillations typically seen in neural pathways in PD.  In the reviewed studies, the electrodes were most commonly placed in the thoracic T7–T12 region or in the cervical C2–C3 region.  The authors concluded that while there may be some benefit to spinal cord stimulation in helping gait disorders in PD patients with neuropathic pain, the results have been mixed in patients without pain.  It is unclear whether relief from pain is what improves gait or if the electrical stimulation has a direct effect on PD.

Much of the literature on this modality consists of case reports.  There have been no double-blinded studies, so it is not known how much improvement was from a placebo effect and at the present time it is unclear if this modality is effective for treating PD.[21]

Summary

PD is a progressive, incurable disease with multiple symptoms.  The only two proven modalities that are generally available to patients to reduce PD symptoms are medications and deep brain electrical stimulation.  The approval of adaptive DBS adds a new dimension to PD treatment that hopefully will improve symptom control.  There is a significant amount of research currently being performed using modalities such as alpha-synuclein reducers, gene therapies, stem cells, neurotrophic factors, MRgFUS, and spinal cord stimulation for PD, but much of this work is preliminary and it may take years to further validate safety and efficacy before they become available outside of a research setting.

Author’s note: Thank you to Theodor Feigelman, MD for editing this article.

---

References

✅ Earn Free CME Credit for Reading This Article

Eligible for 0.5 PRA Category 1 Credit

Click the button below to take a short quiz.

A valid email is required to send your certificate.

We’ll send you occasional updates. Your email stays private—never sold or shared. 😇

Take Test

Earn CME Credit Now

Earn CME Credit NowBUTBU