new parkinson's research

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• RESEARCH HIGHLIGHT
• 20 April 2024

Repurposing a diabetes drug to treat Parkinson’s disease

• Sonia Muliyil

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In a phase 2, double-blind, multicenter randomized control trial conducted in France, 156 patients, 45–70 years of age, with a diagnosis of Parkinson’s disease over the past 3 years and receiving an optimized dopamine regimen, were assigned to receive lixisenatide or placebo once daily for 12 months. Patients who received the drug reported improvements in scores on the Movement Disorder Society–Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) compared with those receiving placebo, as assessed in the on-medication state at 12 months. Although most secondary efficacy outcomes for the trial were no different between the two arms, adverse gastrointestinal effects were reported more frequently in the intervention arm than in the placebo arm.

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doi: https://doi.org/10.1038/d41591-024-00026-0

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• News Release

Newly discovered trigger of Parkinson’s upends common beliefs

Damage starts much earlier than the death of dopamine neurons, scientists report

Media Information

• Release Date: September 15, 2023

CHICAGO --- A new Northwestern Medicine study challenges a common belief in what triggers Parkinson’s disease.

Degeneration of dopaminergic neurons is widely accepted as the first event that leads to Parkinson’s. But the new study suggests that a dysfunction in the neuron’s synapses — the tiny gap across which a neuron can send an impulse to another neuron — leads to deficits in dopamine and precedes the neurodegeneration.

Parkinson’s disease affects 1% to 2% of the population and is characterized by resting tremor, rigidity and bradykinesia (slowness of movement). These motor symptoms are due to the progressive loss of dopaminergic neurons in the midbrain.

The findings, which will be published Sept. 15 in Neuron, open a new avenue for therapies, the scientists said.

“We showed that dopaminergic synapses become dysfunctional before neuronal death occurs,” said lead author Dr. Dimitri Krainc, chair of neurology at Northwestern University Feinberg School of Medicine and director of the Simpson Querrey Center for Neurogenetics. “Based on these findings, we hypothesize that targeting dysfunctional synapses before the neurons are degenerated may represent a better therapeutic strategy.”

The study investigated patient-derived midbrain neurons, which is critical because mouse and human dopamine neurons have a different physiology and findings in the mouse neurons are not translatable to humans, as highlighted in Krainc's research recently published in Science .

Northwestern scientists found that dopaminergic synapses are not functioning correctly in various genetic forms of Parkinson’s disease. This work, together with other recent studies by Krainc’s lab, addresses one of the major gaps in the field: how different genes linked to Parkinson’s lead to degeneration of human dopaminergic neurons.

Neuronal recycling plant

Imagine two workers in a neuronal recycling plant. It’s their job to recycle mitochondria, the energy producers of the cell, that are too old or overworked. If the dysfunctional mitochondria remain in the cell, they can cause cellular dysfunction. The process of recycling or removing these old mitochondria is called mitophagy. The two workers in this recycling process are the genes Parkin and PINK1. In a normal situation, PINK1 activates Parkin to move the old mitochondria into the path to be recycled or disposed of.

It has been well-established that people who carry mutations in both copies of either PINK1 or Parkin develop Parkinson’s disease because of ineffective mitophagy.

The story of two sisters whose disease helped advance Parkinson’s research

Two sisters had the misfortune of being born without the PINK1 gene, because their parents were each missing a copy of the critical gene. This put the sisters at high risk for Parkinson’s disease, but one sister was diagnosed at age 16, while the other was not diagnosed until she was 48.

The reason for the disparity led to an important new discovery by Krainc and his group. The sister who was diagnosed at 16 also had partial loss of Parkin, which, by itself, should not cause Parkinson’s.  

“There must be a complete loss of Parkin to cause Parkinson’s disease. So, why did the sister with only a partial loss of Parkin get the disease more than 30 years earlier?” Krainc asked.

As a result, the scientists realized that Parkin has another important job that had previously been unknown. The gene also functions in a different pathway in the synaptic terminal — unrelated to its recycling work— where it controls dopamine release. With this new understanding of what went wrong for the sister, Northwestern scientists saw a new opportunity to boost Parkin and the potential to prevent the degeneration of dopamine neurons.

“We discovered a new mechanism to activate Parkin in patient neurons,” Krainc said. “Now, we need to develop drugs that stimulate this pathway, correct synaptic dysfunction and hopefully prevent neuronal degeneration in Parkinson’s.”

The first author of the study is Pingping Song, research assistant professor in Krainc’s lab. Other authors are Wesley Peng, Zhong Xie, Daniel Ysselstein, Talia Krainc, Yvette Wong, Niccolò Mencacci, Jeffrey Savas, and D. James Surmeier from Northwestern and Kalle Gehring from McGill University.

The title of the article is “Parkinson’s disease linked parkin mutation disrupts recycling of synaptic vesicles in human dopaminergic neurons.”

This work was supported by National Institutes of Health grants R01NS076054, R3710 NS096241, R35 NS122257 and NS121174, all from the National Institute of Neurological Disorders and Stroke.  

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New Targets and New Technologies in the Treatment of Parkinson’s Disease: A Narrative Review

Nicola montemurro.

1 Department of Neurosurgery, Azienda Ospedaliera Universitaria Pisana (AOUP), University of Pisa, 56100 Pisa, Italy

Nelida Aliaga

2 Medicine Faculty, Austral University, Buenos Aires B1406, Argentina; [email protected] (N.A.); moc.liamg@raircseadnama (A.E.)

Pablo Graff

3 Functional Neurosurgery Program, Department of Neurosurgery, San Miguel Arcángel Hospital, Buenos Aires B1406, Argentina; moc.liamtoh@ffargep

Amanda Escribano

Jafeth lizana.

4 Department of Neurosurgery, Hospital Nacional Guillermo Almenara Irigoyen, Lima 07035, Peru; moc.liamg@anazilhtefaj

5 Medicine Faculty, Universidad Nacional Mayor de San Marcos, Lima 07035, Peru

Parkinson’s disease (PD) is a progressive neurodegenerative disease, whose main neuropathological finding is pars compacta degeneration due to the accumulation of Lewy bodies and Lewy neurites, and subsequent dopamine depletion. This leads to an increase in the activity of the subthalamic nucleus (STN) and the internal globus pallidus (GPi). Understanding functional anatomy is the key to understanding and developing new targets and new technologies that could potentially improve motor and non-motor symptoms in PD. Currently, the classical targets are insufficient to improve the entire wide spectrum of symptoms in PD (especially non-dopaminergic ones) and none are free of the side effects which are not only associated with the procedure, but with the targets themselves. The objective of this narrative review is to show new targets in DBS surgery as well as new technologies that are under study and have shown promising results to date. The aim is to give an overview of these new targets, as well as their limitations, and describe the current studies in this research field in order to review ongoing research that will probably become effective and routine treatments for PD in the near future.

1. Introduction

Parkinson’s disease (PD) is a chronic, progressive, and debilitating neurodegenerative disease that stands as the second most common neurodegenerative disease and affects about 1% of the population aged above 55 years old [ 1 , 2 ]. PD is the most common cause of “parkinsonism”, a syndrome manifested by rest tremor, rigidity, bradykinesia, and postural instability [ 3 ]. These four clinical presentations are commonly present; however, they do not occur long after the disease arises and therefore, they are not included in the Movement Disorder Society (MDS) diagnostic criteria for PD [ 4 , 5 , 6 , 7 , 8 ]. In PD the main neuropathological finding is substantia nigra pars compacta degeneration because of the accumulation of Lewy bodies and Lewy neurites [ 2 , 9 ] and subsequent dopamine depletion [ 10 ].

Deep brain stimulation (DBS) is a technique in which one or more multiple-contact electrodes are implanted in specific brain regions. These electrodes are connected to a subcutaneous implantable pulse generator from which the depolarization, re-polarization and conduction patterns of the neurons’ action potential are electrically modulated. Typically, high frequency stimulation (more than 100 Hz) mainly decreases the ipsilateral discharges from the subthalamic nucleus (STN), but there is also a decrease in contralateral STN nucleus firing [ 11 , 12 , 13 , 14 ]. Moreover, DBS is a three-dimensionally complex phenomenon, and consequently, a decrease in the action potentials in related nearby areas has been reported [ 15 , 16 ]. Even though there are paradoxical in vitro results published in the literature, it is probably because in vitro samples are disconnected from their afferents, so they do not have the chance for orthodromic stimulation [ 17 , 18 ]. However, aside from the DBS effects, it appears to be transient, with several articles suggesting that DBS as well as new technologies may induce long term changes in neuronal properties [ 19 , 20 , 21 ]. Neurochemical differences (GABA, glutamate, DA, cGMP, mGLUR, DR1/DR2) and induction of synaptic plasticity have also been observed in the target and in other related deep nuclei, structures, and the cortex itself [ 16 , 19 , 20 , 21 , 22 , 23 ].

Currently, the FDA (Food and Drug Administration) has approved modulation by DBS in the subthalamic nucleus (STN), the internal globus pallidus (GPi) and the ventralis intermedius nucleus of the thalamus (Vim). Targeting just these classical targets is insufficient for improving the entire wide spectrum of symptoms in PD (especially the non-dopaminergic ones), and none are free of the side effects which are associated not only with the procedure, but with the targets themselves. However, new targets and new technologies that could potentially improve the motor and non-motor symptoms of PD are currently proposed in the literature and are here discussed.

2. Overview of Basal Ganglia Functional Anatomy

The classical model of the basal ganglia includes both the direct and indirect pathways [ 24 , 25 , 26 ]. Both pathways are modulated by dopamine from the SNc (nigrofugal pathway) which sends projections to the posterior putamen, which in turn sends GABA projections back to the SNc. In addition, the motor cortex, the somatosensory cortex and the STN send glutamatergic fibers to the SNc [ 24 , 26 , 27 ]. However, there is evidence that the striatofugal pathways (direct and indirect) can no longer be considered dual, due to complex and extensive networks with advanced patterns of bridging collaterals ( Figure 1 ) [ 28 ]. This provides straightforward evidence of the overlap and the delicate balance between both pathways [ 28 , 29 ]. Additionally, it is known that there are different functional regions in the striatum and the pallidum for the sensorimotor, associative, and limbic components [ 30 ]. For example, the head and the tail of the caudate have mainly associative fibers, while the putamen has mostly sensorimotor connections. Additionally, the ventral striatum has predominantly associative fibers and is also related to the limbic system [ 30 , 31 ]. However, in the end it is difficult to draw a boundary line between the dorsal and the ventral striatum, as well as between the functionality of each one [ 30 ].

This figure shows a coronal section of the basal ganglia circuit with emphasis on its complex connections. Illustrated by J. Lizana.

The pallidofugal pathway is related to symptoms such as tremor and stiffness [ 32 ] and it is also known that 90% of cells that make up the GPi are motor neurons which connect to the PPN, ventral and CM/PF nuclei of the thalamus; however, there are 10% of limbic neurons that reach the lateral habenula [ 25 ]. Traditionally, it was believed that in the pallidofugal pathway the bipolar neurons at the lateral GPi would send their axons to the thalamus through the lenticular fasciculus and the ansa lenticularis, while neurons at the medial GPi would only send their axons through the lenticular fasciculus, and the GPe would send its efferents through the subthalamic fasciculus to reach the STN ( Figure 2 a) [ 25 , 33 , 34 ]. Nevertheless, there is evidence that the pallidofugal pathway fibers from the dorsal part of the GPi travel through the lenticular fasciculus, then pass between the STN and the ZI to finally reach the ventral part of the thalamus, while the fibers from the intermediate part of the GPi travel through the pallidum subthalamic tract and reach the lateral STN side [ 25 , 33 , 35 ]. Finally, the axons from the ventral part of the GPi travel through the ansa lenticularis then connect to the SN and continue to the brainstem through the fasciculus Q of Sano or the pallido tegmentalis, while other fibers of the ansa lenticularis turn dorsally to reach the thalamus through the thalamic fasciculus ( Figure 2 b) [ 35 ]. In the case of the GPe, there is a description of a direct projection to the frontal regions of the cerebral cortex, the caudate and the putamen [ 34 , 36 ].

Figure ( a ) depicts the classical pallidofugal pathways, while Figure ( b ) illustrates some changes in the recent understanding of how the Globus pallidus communicates with other basal ganglia structures. Illustrated by J. Lizana.

With regards to the cerebral cortex, its connections with the basal ganglia are also well known (Corticofugal pathway). For instance, the prefrontal cortex has connections with the caudate’s head; however, the dorsolateral prefrontal cortex and the pre-supplementary motor area are related to the anterior putamen [ 2 , 26 ]. Meanwhile, the limbic cortical areas that are connected to the ventral striatum and the motor cortex by the corticostriatal pathway, reach the posterior putamen [ 2 , 26 , 30 ]. The study of these pathways resulted in the identification of the glutamatergic hyperdirect cortico-subthalamo-pallidal circuit which plays a very important role in DBS procedures [ 24 , 37 ]. Furthermore, functional images have provided evidence of cerebellar activation in a wide variety of motor and non-motor processes [ 38 , 39 , 40 , 41 ]. It has been proved that a lot of cortical areas and basal ganglia nuclei, which are targets of cerebellar output, also project back onto the cerebellum ( Figure 3 ) [ 40 , 42 , 43 ]. STN DBS may not only normalize the functional activity of the associative and limbic cerebellar cortices and decrease the activity of Purkinje cells with consequent disinhibition of the cerebellar nuclei, but could also improve some non-motor symptoms [ 40 , 44 , 45 ]. There is also evidence that STN DBS in dystonia, Tourette syndrome and PD results in decreased cerebellar hypermetabolism and symptom improvement [ 40 ]. Research in functional neuroanatomy has allowed critical advances in the development of new devices as well as the possibility of new targets.

A sagittal section of the brain, trunk and cerebellum shows the complex connections between basal ganglia and cerebellum. AMY, Amygdala; BC, Brain cortex; CC, Cerebellar cortex; CiC, Cingulate cortex; CN, Caudate nucleus; DN, Dentate nucleus; FN, Fastigial nucleus; GPe, External globus pallidus; GPi, Internal globus pallidus; IN, Interpositus nucleus; NAcc, Nucleus accumbens; NBM, Nucleus basalis of Meynert; PN, Pontine nuclei; PUT, Putamen; RN, Red nucleus; STH, Subthalamus; THA, Thalamus. Illustrated by J. Lizana.

3. New DBS Targets

3.1. pedunculopontine nucleus.

The pontine peduncle nucleus (PPN) is a motor center of the trunk that is related to the initiation and modulation of the gait and receives afferents from the cortex, the central core, the trunk, and the medulla [ 46 , 47 ]. The PPN consists of the Cholinergic Pars Compacta (PPNc) and the Pars Dissipatus (glutamatergic and cholinergic) [ 47 ] and it is located medially to the middle lemniscus and laterally to the decussation of the superior cerebellar peduncle. Its rostral portion is posterior to the SN and the RRF, while its caudal pole meets the reticular formation, the cuneiform nucleus, and the locus coeruleus [ 48 ]. It has been observed that low-frequency stimulation of the PPN (bilateral or unilateral) inhibits the GABAergic neurons of this nucleus, which allows their activation and increases movement [ 47 , 49 , 50 ]. It is important to note that this nucleus may be involved in PD. However, the stimulation of this area may compromise adjacent structures such as the caudal portion of the mesencephalic reticular formation [ 47 , 48 , 49 , 51 ]. In many cases, DBS of the PPN has had good results on different aspects of the gait and appears to be a safe target [ 51 ]. Nevertheless, this effect is not uniform in all studies, nor in all patients [ 52 , 53 , 54 ].

3.2. Zona Incerta

The caudal zona incerta is a known target and is part of a region called the posterior subthalamic area, which is located posteromedial to the STN, inferior to the thalamus and lateral to the red nucleus [ 9 ]. It has been observed in studies carried out in patients with STN-DBS, that stimulation of this area and the adjacent ones (pallidothalamic fibers) improves the results, which contrasts with patients where only the STN is stimulated, thus developing interest in the surrounding structures (the zona incerta) as a possible therapeutic target since it is a unique GABAergic link between the basal ganglia output nuclei, the cerebello-thalamo-cortical loop and the brainstem nuclei [ 55 , 56 , 57 , 58 ].

Due to their interconnections with the basal ganglia and the cerebellum ( Figure 1 ), stimulation of the zona incerta (incerto-thalamic fibers) and the bundles that cross this area (the nigrothalamic fibers, the incerto-pallidal bundle, the pallidal-thalamic pathway and the cerebellar-thalamic tract) improves, importantly, symptoms such as essential voice tremor compared to STN stimulation [ 46 , 59 ], and also results in decreases in bradykinesia, rigidity, ataxia and abnormal muscle activities [ 60 , 61 ]. Moreover, stimulating the ZI and adjacent areas decreases the required dose, and reduces the adverse effects, of dopaminergic medication [ 62 ]. Other points in favor of this target are that it is relatively easy for neurosurgeons to leave the deep ventral DBS contact in the caudal ZI, and that long term studies have shown that the ZI does not develop tolerance; however, Vim DBS did provide better outcomes [ 61 , 63 ]. However, it is necessary to highlight that it can cause or exacerbate dyskinesia, dysarthria, and can also alter pleasure-seeking behavior [ 60 , 64 ]. There are limitations to these findings with regards to it being a new target so it is a procedure rarely performed and with few studies on the subject, as such, we cannot define conclusions [ 61 , 63 ].

3.3. Thalamic CM/Pf Complex

The thalamus as a target (Vim) for DBS was the first to be studied and applied in clinical practice and demonstrated adequate control of the tremor at rest [ 65 ]. The centromedian/parafascicular complex (CM/Pf) is located in the posterior intralaminar thalamus [ 66 , 67 ]. It is an important center for sensory, limbic and motor processing association due to its extensive connections with the cortex, the basal ganglia and the brainstem [ 66 ]. It has been observed in patients whose dyskinesia improves that the thalamic electrode is closer to the CM/Pf than to the Vim [ 67 , 68 ]. Similarly, clinical improvement has been highlighted in tremor and freezing of gait, motivating interest in its role in DBS surgery [ 69 , 70 ]. Although it does not affect extrapyramidal symptoms with the same intensity as DBS of the STN, it seems to be a better target than the Vim and it opens up the possibility of a synergistic and complementary effect with other targets for patients with difficult-to-control symptoms [ 67 , 69 , 70 , 71 ].

3.4. Substantia Nigra Pars Reticulata (SNr)

The midbrain locomotor region is a functional territory that appears to be comprised of both the cuneiform nucleus and part of the PPN and is directly influenced by GABAergic nigro-tegmental projections from the SNr in addition to the supplemental motor cortex [ 72 , 73 ]. This relationship of the SNr with the ponto-mesencephalic and spinal structures motivated experimental studies where it was observed that both its unilateral and bilateral stimulation (and in many of these cases combining its effect with the stimulation of the STN), could favor the improvement of axial symptoms related to the onset of gait in patients with PD [ 72 , 74 ]. Furthermore, an improvement has also been noted in the axial symptom subsection of the UPDRS scale, thus constituting a potential tool for the treatment of postural instability and freezing of the gait [ 73 , 75 , 76 ]. However, psychiatric side effects (acute depression, hypomania and mania) have been reported in a variable way and are possibly related to its limbic connections [ 73 ].

3.5. Multitarget

Multitarget therapy is a novel and interesting option that involves more than one anatomical objective for patients in whom the most common targets such as STN or GPi, by themselves, are insufficient for controlling the symptoms of the disease, mostly, non-dopaminergic symptoms such as gait, balance impairment and cognitive decline [ 46 , 77 , 78 ]. As detailed in the previous sections, the use of new targets such as the PPN, the ZI, the SNr and the thalamus for DBS is under investigation [ 54 ]. These options are open to different therapeutic scenarios for the management of complex cases. If their effectiveness is demonstrated, it is most likely that they will not replace the classical targets but will be used as adjuvants in selected cases [ 79 ]. Similarly, it is possible to combine the stimulation of two classical targets such as the STN and the GPi to obtain better results [ 80 ]. The development of multitarget therapy is based on the improvement of surgical times, technological progress and the clinical benefits associated with biochemical changes in areas other than the STN for the legitimate control of clinical signs that cannot be controlled with classical DBS targets [ 70 , 80 ]. Candidates for multitarget therapy are patients with involuntary movements who are reluctant to decrease their dose of drugs; patients with severe tremor whose response to STN-DBS progressively decreases; patients freezing in ON periods; and even patients with mild cognitive impairment whose eligibility for STN-DBS may be in doubt [ 80 ].

One of the advantages of GPi/STN-DBS in PD is that it offers greater control of neuropsychiatric symptoms. [ 46 , 70 ] Currently, a GPi/STN-DBS strategy is more than an eligible approach for those cases where there is profound and medically refractory functional impairment [ 78 , 81 ]. GPi/STN-DBS has shown favorable outcomes; however, its effect has been seen to decrease over time. For this reason, more evidence is needed to fully understand the advantages and limitations of this dual stimulation [ 78 ]. Treating multiple targets with DBS is limited by its higher costs, the prolonged inconvenience of surgery due to its slower result, greater probability of complications, and the requirement of multidisciplinary and highly specialized healthcare staff for peri- and post-operative management [ 70 , 77 ]. This review is susceptible to changes through time, as technology and science become more advanced and new research will be reported in the near future.

4. Non-Invasive and Minimally Invasive Treatment

4.1. endovascular approach.

The use of endovascular devices (with cable or without cable) with the ability to record brain activity and stimulate adjacent tissue (STENTrodes) has emerged as an alternative among mechanisms of deep stimulation with minimal invasion for the treatment of PD, essential tremor, epilepsy, severe paralysis and many other diseases [ 82 , 83 ]. There is a wide variety of catheters, guide catheters, microcatheters and micro guides, among others, which facilitate the release of the devices in the desired location [ 82 , 84 ]. The endovascular routes for the release of the device can be by a transarterial or transvenous route [ 83 ]. However, the anatomical variations of the vascular structures are a limitation for the adequate positioning of the device, since precise planning for the identification of an accessible vascular structure (vessels with a diameter greater than 1 mm are more accessible) closest to the target is essential. Angiography and MRI protocols have taken on a greater relevance for the elaboration of probabilistic maps in order to improve the accuracy of the device placement [ 83 , 85 , 86 ]. Only some structures such as the nucleus accumbens, fornix, subcallosal cortex of the cingulum, dentato-rubro-thalamic tract, subthalamus and pontine peduncle nucleus, among others, are susceptible to stimulation by this route due to their vascular proximity [ 83 , 87 ] ( Figure 4 ). It should be noted that the possibility of performing the procedure with the patient awake allows for evaluation of the procedure and observing whether the result is the desired one [ 88 ]. Although endovascular therapy has an encouraging future due to new and continuous advances, it must be considered that there are potential side effects depending on the location of the device, ranging from psychiatric disorders (due to proximity to the limbic system) to autonomic problems (due to proximity to the hypothalamus), and also those of the procedure such as intracranial hemorrhage and arterial or venous thrombosis by the intraluminal device (with SHIELD technology the thrombogenicity of the devices is reduced) [ 82 , 83 , 87 , 89 ].

This figure shows some theoretical locations (superior sagittal sinus, internal cerebral vein and basal vein of Rosenthal) of STENTrodes which can be placed by the endovascular transvenous approach to stimulate the cortex, thalamus or brainstem nuclei. Illustrated by J. Lizana.

4.2. Non-Invasive Transcranial Stimulation

Non-invasive transcranial stimulation is based on beta oscillatory activity (14–35 Hz anti-kinetic activity) that occurs at the level of the motor cortex and its connections with the basal ganglia (predominantly with the subthalamus and the GPe) [ 90 , 91 , 92 ]. These connections are exacerbated (excessive beta synchronization) in patients with PD [ 91 , 92 , 93 , 94 ]. This abnormal activity occurs mainly during involuntary tonic contractions and decreases with voluntary motor activity (beta desynchronization), as well as with pharmacological and surgical treatment [ 91 , 92 , 93 , 94 ].

Currently, there are two techniques known as “Non-invasive transcranial stimulation”: The first one, Transcranial Current Magnetic Stimulation (TMS) and the second one, Transcranial Current Stimulation (tCS) [ 95 , 96 ]. Both have proved to have a good efficacy rate in the modulation of cerebral activity [ 95 , 96 , 97 ]. One of the advantages of this non-invasive technology over DBS is that it can target cortical and subcortical structures; therefore, it can reach remote locations from the stimulation site [ 96 , 98 ]. It should also be mentioned that DBS is an invasive procedure, consequently, it goes hand in hand with some complications, such as infection, limited duration of electrical components, neural immune system reactions, and the need for periodic battery replacement [ 99 , 100 , 101 , 102 ]. One of the limitations of TMS is that this device is large and heavy, whereas tDCS is light and small, which makes it more feasible since it is a treatment that does not require hospitalization and the sessions can be performed at the patient’s home [ 97 , 103 ]. Cost is another big difference, with TMS systems costing between $20,000 and $100,000, while tDCS devices have prices ranging from $400 to $10,000 [ 95 , 97 , 104 ].

4.2.1. Transcranial Magnetic Stimulation (TMS)

TMS is a well-tolerated and painless brain stimulation technique in which a strong and rapidly changing electromagnetic field is generated [ 95 , 97 , 103 , 105 ]. This electromagnetic field induces strong and short-lived electrical currents, which initiate action potentials in both the cortex and subcortical white matter [ 96 , 97 , 105 ]. The application of repetitive transcranial magnetic stimulation (rTMS) is able to induce lasting changes in cortical excitability, which represents a promising tool against neuropsychiatric alterations and motor symptoms in PD [ 98 , 104 , 106 ]. Unlike TMS, rTMS appears to be more effective in stimulating the association cortex [ 107 ]. Presently, TMS has a larger number of published studies demonstrating its safety in terms of effects on brain anatomy and biochemistry, than does tDCS [ 97 , 105 ]. Other studies being conducted, which link rTMS with an improvement in non-motor symptoms in PD such as cognitive dysfunction, speech difficulty and depression, show mixed results [ 105 , 107 ]. However, its greatest risk is the induction of seizures [ 108 ]. Preclinical data on the safety of TMS is still very limited, and rTMS protocols are needed to use this technology as a routine treatment for PD [ 95 , 98 ].

4.2.2. Transcranial Current Stimulation—Transcranial Direct Current Stimulation (tDCS)

TCS has re-emerged as a form of non-invasive modulation of spontaneous neuronal activity by applying a weak electrical current (1–2 mA) through the placement of two or more electrodes on the scalp, allowing regulation of neuronal membrane potentials (changes in discharge probability), changes in neurotransmitters, glia, and micro vessels [ 109 ]. In other words, it provides neuronal plasticity, shown by the generation of long-term synaptic potentiation (objectified by the increase in brain derived neurotrophic factor (BDNF) secretion and TrkB activation) when combined with repetitive low-frequency synaptic activation [ 110 ]. Transcranial direct current stimulation (tDCS) affects the motor symptoms of the disease, with the most prominent results related to rehabilitation. However, its usefulness is limited due to its weak effects, high variability, and lack of consensus in protocols, with medication status being a key cofounder in determining the level of efficacy [ 111 ].

4.2.3. Transcranial Current Stimulation—Transcranial Stimulation with Alternating Current (tACS)

Recent innovations in transcranial alternating current stimulation (tACS) offer new areas of research [ 111 ]. This is a variant of direct cranial stimulation and consists of the interference of sinus waves for the modulation of brain oscillations (physiological brain activity in an area) [ 109 , 111 ]. It has been observed that tACS has a different effect on healthy people compared to those with PD due to its effect on beta synchronization [ 92 , 112 ]. tACS seems to produce an improvement in motor symptoms in people with PD, which is further enhanced when associated with a closed loop system [ 92 ]. Furthermore, when this device stimulates the cerebellum, it also results in the modulation of parkinsonian tremor [ 113 ]. In addition to this, there is evidence that, like tDCS, it not only modulates brain activity, but also seems to generate cortical neuronal plasticity [ 114 , 115 , 116 ].

4.3. Non-Invasive Focused Ultrasound

Magnetic resonance-guided focused ultrasound (MRgFUS) is a novel, non-invasive procedure for symptomatic treatment of PD [ 117 , 118 ]. Two types of focused ultrasound therapy are recognized. The first one is called non-ablative: this technology has potential uses in pain neuromodulation, epilepsy, and is also seen as a new strategy to allow the passage of medication through the BBB, for instance, biological-genetic treatment in PD [ 117 , 119 ]. The second one is ablative ultrasound, in which two varieties are differentiated according to the frequency used. High intensity focused ultrasound (HIFU) produces thermal ablation in small brain targeted areas (therapeutic sonication) [ 118 , 120 ]. This technology enables accurate targeting by using a real-time MRI for morphological and thermal monitoring [ 120 , 121 ]. On the other hand, ablation at low frequencies is due to a fast change in the targeted tissue pressure, forming gas–vapor filled cavities. These cavitation bubbles oscillate at large amplitudes and exert shear stresses on the surrounding tissue, causing the mechanical cell membranes to tear (histotripsy) [ 119 , 122 , 123 ].

The use of HIFU in the Vim nucleus has been approved by the FDA for the treatment of tremor in patients with PD [ 117 , 120 , 124 ]. Candidate patients for Vim ablation are those with very asymmetric symptoms, who are not able to have or do not want surgery or implants, but does not including patients with refractory tremor. Exclusion criteria are severe bilateral axial symptoms, severe dyskinesia, cognitive impairment, or psychiatric illness [ 117 ]. Although unilateral ablation of the Vim seems to be effective, it has transitory side effects such as weakness, gait, and speech disturbances [ 120 ]. The STN is a potential target for MRgFUS; however, due to few studies being available, it cannot be considered as strong evidence. This procedure has a high rate of adverse effects, with gait instability being the most frequent; however, all are mostly transient [ 117 , 120 , 125 ]. Similarly, the results of GPi ablation in patients with PD is little but encouraging due to the effects its ablation has on dyskinesias, as well as the improvement of PD symptoms in off-L-dopa state patients [ 117 , 126 ]. Furthermore, challenges lie ahead in treating this target due to its proximity to the optic nerve and being able to correctly target the ultrasound rays on the treatment area [ 118 , 127 ].

The advantages of MRgFUS over DBS are that this non-invasive technology does not carry any risk of infection or hardware failure, and post-operative programming is not required as the effect is achieved immediately at the end of the procedure [ 120 , 128 ]. What is more, this procedure does not include any kind of brain penetration, therefore, it does not have the complications associated with foreign object implantation [ 120 , 129 , 130 ]. Gamma knife use also effectively suppresses tremor but is limited by the latent effects of radiation and the inability to target intraoperatively [ 130 ]. Nevertheless, some disadvantages of MRgFUS lie in its local effects, such as headache, scalp burns, and bone necrosis [ 123 ].

5. Regenerative Medicine in Parkinson Disease

Currently, none of the pharmacological or surgical treatments can cure or modify the neurodegeneration process that occurs in PD [ 131 , 132 ]. Furthermore, it is known that the current management of PD is insufficient and costs billions to the world economy. In the USA alone, the cost of PD is 35 billion annually and it is estimated that by stopping its progression, the economic benefit would be almost 450,000 dollars per patient [ 133 ]. Regenerative medicine has been progressively developed in recent decades with the aim of reconstructing and restoring the functionality of highly sophisticated neural circuits (connectome) that are lost in PD [ 131 , 132 , 134 , 135 ]. Technological progress in cell engineering, cell programming, immunomodulation, tissue engineering, biomaterials, gene therapy, and stem cells has allowed the development of several studies that project a promising future in this type of biological therapy [ 136 , 137 , 138 , 139 , 140 ].

5.1. Gene, Cell, and Tissue Regenerative Therapies

Autologous or heterologous cell transplantation with neural differentiation potential has shown satisfactory results in animals and humans [ 136 , 141 , 142 ]. Different cell types can be divided into these groups: fetal mesencephalic cells, adrenal medullary cells, carotid body cells, sympathetic ganglia cells, and retinal pigmentary epithelial cells [ 142 , 143 ]. Human fetal mesencephalic tissue grafts are the ones with the most evidence and the greatest success (documented improvement of motor symptoms) to date [ 144 , 145 , 146 ]. The objectives of this type of therapy are the survival of dopaminergic cells, afferent and efferent synaptic integration, and adequate and controlled dopamine release, in addition to the clinical improvement of patients [ 136 , 141 , 147 ]. There are reports of patients in whom the presence of transplanted cells has been demonstrated up to 24 years later; however, their potential susceptibility to degeneration is still not clear [ 145 , 148 ]. The problems with the clinical studies involving fetal mesencephalic cells include: the heterogeneity of the cells, in most cases the transplant has not been performed in the SNc region but in the striatum, there is a well-known limitation in the availability of fetal tissue, cells do not always differentiate as expected, it has been observed that the grafts are not made up purely of dopaminergic cells, this kind of procedure often requires immunosuppression, and there are underlying ethical considerations [ 142 , 149 , 150 , 151 ]. Another risk in the use of stem cells is the neoformation of tumors and the development of graft-induced dyskinesia (GID) [ 152 , 153 , 154 ].

There are other sources of cells with potential dopaminergic differentiation such as embryonic stem cells (ESC), induced pluripotential stem cells (iPSC), neural precursor cells (NPC), mesenchymal stem cells (MSC), and direct neuronal reprogramming [ 152 , 155 , 156 ]. ESCs come from early-stage embryos, which implies ethical problems, limited availability, and they have a significant risk of tumor development [ 152 ]. Knowledge of cell de-differentiation techniques as well as advances in neurodevelopment have allowed the generation of iPSCs with greater similarity to dopaminergic neurons and with a lower oncological risk [ 156 , 157 ]. NSC can be induced from iPSC and because of their limited differentiation capability they have less oncogenic likelihood [ 158 ]. On the other hand, MSCs have a more limiting potential for neural differentiation but have an immunomodulatory effect that counteracts neurodegeneration [ 159 ]. Problems with earlier grafts have generated an increased interest in neuronal reprogramming, in which virus vectors, microRNAs, or transcription factors can be used to alter the gene expression in astrocytes in order to generate dopaminergic neurons [ 138 , 140 ].

Despite advances in cell restoration, there is a gap to recover the lost functionality, that is, the development of new and appropriate neuronal circuits which maintain the dopaminergic function [ 139 , 160 , 161 , 162 , 163 ]. Axonal growth over long distances, its directionality, and the reinnervation of the correct target continue to be a matter of investigation [ 160 , 164 , 165 , 166 , 167 ]. Nowadays, chemoattractant factors are being used in the striatum to promote the restructuring of the nigrostriatal pathway [ 165 ]. Other strategies include the use of embryonic striatal tissue, renal tissue, kainate injections, and overexpression of GDNF (glial cell line-derived neurotrophic factor) in the striatum by virus vectors [ 168 , 169 ]. The development of new micro biomaterials has allowed the creation of scaffolds for grafts, that not only protect and promote the graft growth but can also be implanted in the form of neural networks that stimulate the nigrostriatal pathway and favor its restoration [ 139 , 160 , 170 ]. Finally, there is a potential risk that any cell or tissue engineering strategy may succumb to the underlying pathology and degenerate in a similar way to the original tissue, so developing new grafts resistant to different stress factors is a new objective [ 151 , 171 , 172 ].

5.2. Optogenetic Therapy

The lack of control over the delimitation of the stimulated area can lead to undesirable results [ 173 , 174 ]. Due to this problem, optogenetic therapy has emerged as an interesting option to avoid side effects due to the stimulation of structures adjacent to the target [ 175 ]. This therapy consists of the use of genetically altered viruses with the aim of modifying neuronal genes (the gene for an ultra-fast opsin called Chronos is packaged in the adeno-associated virus type V with a CaMKII promoter for a local effect on the subthalamic nucleus) and making them susceptible to excitation or inhibition by light, so that the desired effect is generated in a more controlled way in each area [ 171 , 172 , 173 , 174 , 175 ]. Optogenetic therapy opens a way for us to understand synaptic and circuit properties on a mechanistic level [ 176 , 177 ]. Favorable results in several animal studies lead us to believe that this therapy could be an important research tool for future DBS-based therapies, leading to symptoms being resolved, and not masking them [ 174 , 178 ]. However, to date this technique is not yet feasible in humans and suffers from other limitations such as light stimulation parameters (duration, frequency, and intensity of stimulation) which must be managed carefully to avoid problems such as depolarization blocks or rebound excitation [ 177 , 179 , 180 , 181 ]. We hope that one day this could be a viable treatment for movement disorders.

6. Discussion and Conclusions

Research into functional anatomy as well as clinical trials have allowed a better understanding of the basis, benefits, and limitations of DBS procedures [ 24 , 26 , 38 ]. The most common scope of studies in PD is directed towards motor symptoms [ 132 ]. However, non-motor symptoms are as relevant as these but less studied and, due to their great impact on quality of life, they require more intensive research [ 73 , 132 ]. Currently, progress in the development of devices is reflected in increasingly personalized treatments and the approach of new targets [ 46 , 77 ]. Although most of these targets require more evidence for their widespread use, they open the possibility of being associated with classical targets to achieve better symptom control [ 79 , 80 ]. One of the main disadvantages of DBS is the high cost involved while newer devices appear to be cheaper [ 92 , 104 , 133 ]. In addition, several of these new devices offer the advantage of being minimally invasive or non-invasive at all [ 85 , 87 , 105 ].

Accelerated advances in biological therapy, gene therapy, cell engineering, tissue engineering, and biomaterials have made it possible to propose new therapeutic options with the potential to modify the course of the disease [ 134 , 140 , 160 ]. Even though several studies have shown encouraging long-term results with the use of embryonic or fetal human cells, the limitations and risks of this type of graft have motivated the development of techniques for the induction of new cells with dopaminergic potential [ 151 , 156 , 157 ]. Nevertheless, we must consider that both the management of fetal or embryonic tissue, as well as genetic manipulation at the cellular or viral level, entail ethical considerations and risks [ 152 , 155 , 169 ]. The development and use of biomaterials in the peripheral nervous system is currently quite widespread; however, the central nervous system constitutes a more complex area for their use. The accuracy in the design, its microstructure that tries to reproduce the neural circuits, and the advantages shown in the studies are encouraging [ 164 , 169 ]. Most current studies are focused on technological advances, but this should not be separated from the study of functional micro neuroanatomy, since the integration and deepening of both will allow for better results.

There is parallel improvement in regenerative and non-regenerative treatment. Non-regenerative treatment seeks to improve the performance, invasiveness issues, and duration of its devices [ 46 , 77 , 96 ]. However, it has not been shown to affect the disease progression [ 118 ]. Merely stopping its progression would generate a major impact, but current initiatives go beyond that and seek to regenerate the tissue and lost connections, that is, to cure it [ 133 , 160 ]. As described, the new therapeutic options also have limitations and problems, but under the same logic of multitarget treatment, with the wide range of current options, studies of multimodal or hybrid management in PD should be considered. We believe that the treatment of PD will no longer be symptomatic related in due time and that the future directions of surgical management of PD are towards regenerative neurosurgery. We have described the current studies and ongoing research in PD in order to review the treatments that may become effective and safe in the near future for the treatment of PD.

Funding Statement

This research received no external funding.

Author Contributions

Conceptualization, J.L., N.A., P.G. and N.M.; methodology, N.A. and N.M.; validation, J.L., N.A. and A.E.; formal analysis, J.L., N.A. and P.G.; writing—original draft preparation, J.L., N.A., P.G. and N.M.; writing—review and editing, J.L., N.A., A.E. and N.M.; visualization, J.L.; supervision, J.L., N.A. and N.M. All authors have read and agreed to the published version of the manuscript.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Conflicts of interest.

The authors declare no conflict of interest.

Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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Highlights from APDA-funded Parkinson’s Research: 2023 Update

APDA-Funded Research Projects: 2023 Update

Since 1961, APDA has been a funding partner in many major scientific breakthroughs and has  awarded nearly $60 million in Parkinson’s disease (PD) research grants  to date.

Every year, APDA funds individual research grants and fellowships awarded to scientists performing innovative PD research. APDA also funds Centers for Advanced Research, large PD research programs at major medical institutions involved in early-stage drug discovery programs, clinical trials, and movement disorders fellowship training. These Centers facilitate research at the forefront of investigations into the causes, treatments, and finding the cure(s) for Parkinson’s disease.

Grants are awarded through a competitive application process and reviewed by APDA’s  Scientific Advisory Board  (SAB). The SAB is an impressive group of accomplished scientists with a wide array of backgrounds and expertise in all areas relevant to PD research.

Today, we will highlight three recently published research findings that can be attributed to APDA funding. We know the PD community is eager to learn about any research progress being made! Last year, we also highlighted three published APDA research projects and presented the cumulative impact of our research money.

You can also read about other APDA-funded researchers and their continued success in two previous blog posts:

• Where are They Now? APDA’s Research Success
• Where are They Now? APDA’s Research Success, Part 2

Recent APDA Research Success

Cognitive behavioral therapy via telehealth.

Dr. Bonnie Wong is a Clinical Associate Professor in the Department of Psychological and Brain Sciences at Boston University and directs the Interventional Neuropsychology Group at the Center for Anxiety and Related Disorders. She received an APDA Research grant in 2019 to conduct a clinical trial for alleviating depression and cognitive impairment in PD through cognitive behavioral therapy (CBT) conducted via telehealth. Recently, she published a paper entitled Telehealth Transdiagnostic Cognitive Behavioral Therapy for Depression in Parkinson’s Disease: A Pilot Randomized Controlled Trial , which chronicled the results of a randomized controlled trial evaluating the efficacy, feasibility, and acceptability of telehealth cognitive behavioral therapy for people with PD. The intervention was shown to be effective for treating depression with secondary benefits to anxiety, apathy, learning, memory, and quality of life.

These findings are vital since there are not sufficient mental health professionals in the United States who understand the complexities PD, and these professionals are not located everywhere in the country. Knowing that CBT can be conducted successfully over telehealth is the next step in making this therapy available to many more people across the country.

GBA Mutations & the Development of PD

Dr. Giulietta Riboldi is an Assistant Professor in the Department of Neurology and the Director of the Clinical Research and Genetics of the Movement Disorders Division at NYU Langone Health in New York. She received a post-doctoral fellowship from APDA in 2018 to study the role of glucocerebrosidase (GBA) mutations in the development of PD and we highlighted Dr. Riboldi’s work in 2019. Her project focused on the genomic profile of monocytes, a cell type of the immune system that circulates in the blood and which is thought to play a role in the pathogenesis of PD. The genetic differences in the monocytes of four groups were studied – people with PD without a GBA mutation, people with PD with a GBA mutation, people without PD with a GBA mutation, and people without PD and without a GBA mutation.

Recently, the results of this work were published , and showed several interesting findings. In comparing people with PD with a GBA mutation vs people without PD with a GBA mutation, those who developed PD had dysregulation in genes involved in alpha-synuclein degradation, aging, and amyloid processing. In addition, there was dysregulation of genes involved in lysosomal function, membrane trafficking and mitochondrial processing. This information is crucial as it builds on our understanding about how a GBA mutation leads to PD in some people but not others. By understanding the steps that go wrong that lead to PD, we can figure out new ways to intervene in that process.

Lewy Bodies & Dementia

The APDA Center for Advanced Research at Washington University in St. Louis is directed by Dr. Joel Perlmutter, who is also a valued member of APDA’s Scientific Advisory Board . APDA’s financial support of the Center led to several recent publications this year, including a study analyzing the relationship between Lewy bodies in the brains of people with PD and dementia.

The Movement Disorders Center at Washington University maintains a brain bank, which performs autopsies on brains of people with a diagnosis of PD or a related disorder during life. The data from these brains, collected between 1996 and 2019, was correlated with the clinical data maintained on these individuals when they saw their movement disorders physician at Washington University.

One hundred and sixty-five people were included in the study and the presence of Lewy bodies (abnormal cellular deposits of the protein alpha-synuclein and thought to be the pathologic hallmark of PD) was assessed. Six percent of individuals with PD and dementia did not have neocortical Lewy bodies (Lewy bodies in the thinking parts of the brain). On the other hand, 68% of the individuals with PD but without dementia had neocortical Lewy bodies. So, although neocortical Lewy bodies almost always accompany dementia in PD, they also appear in most PD patients without dementia. And in some cases, dementia may occur in patients with PD without neocortical Lewy bodies.

The paper concludes that:

• additional factors besides neocortical Lewy bodies are necessary to cause dementia in PD
• additional factors are protective against dementia when neocortical Lewy bodies are present in PD
• in some people with PD, Lewy bodies are not a factor at all

This is fundamental information to help us understand the elements that may contribute to, as well as alleviate, dementia in PD.  

APDA-Funded Research and Findings

We applaud all our APDA-funded researchers and their contributions to our understanding of Parkinson’s disease. We look forward to their future discoveries.

Tips & Takeaways

• Drs. Bonnie Wong, Giulietta Riboldi and Joel Perlmutter recently published findings that emerged from their APDA-funded projects.
• APDA can fund these researchers because of the  generous donations  we receive from dedicated people like you. If you would like to support critical work like this, please consider  donating  of any size today.
• To learn more about APDA’s research funding, please visit the  What We Fund  section of our website.

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Study discovers potential biomarkers of environmental exposures in parkinson’s disease  .

A team of Northwestern Medicine investigators has discovered novel DNA methylation patterns in the blood of patients with Parkinson’s disease, according to findings published in Annals of Neurology.   

The study, led by Paulina Gonzalez-Latapi, MD, MS , assistant professor in the Ken and Ruth Davee Department of Neurology ’s Division of Movement Disorders , demonstrates the potential of utilizing DNA methylation as a biomarker and diagnostic tool for identifying disease risk in patients.  

Parkinson’s disease occurs when specific regions of the brain lose their ability to make dopamine and, ultimately, regulate movement. The condition impacts more than six million people worldwide, according to the Michael J. Fox Foundation for Parkinson’s Research.  

In addition to currently known genetic causes of Parkinson’s, recent work has also suggested that environmental factors can increase one’s risk of developing the disease. Understanding the impact of environmental exposures and genetic mutations on disease risk, however, has remained understudied.  

In the current study, the investigators studied DNA methylation profiles from the blood samples of 196 patients with Parkinson’s disease and 86 healthy controls enrolled in the Parkinson’s Progression Markers Initiative ( PPMI ) study.  

“DNA methylation in some ways serves as a memory of prior environmental exposures that ultimately alter methylation signatures in our cells and body,” Gonzalez-Latapi said.  

First, the investigators analyzed genome-wide methylation data to identify methylation changes in participants’ whole blood samples (consisting of red blood cells, white blood cells and platelets) over the three-year study period. They then integrated these data with gene expression data obtained through RNA sequencing. 

By utilizing approaches, the team discovered 75 differentially expressed genes with different methylation patterns in Parkinson’s patients compared to healthy controls.  

Notably, they found consistent differences in DNA methylation within the CYP2E1 gene from the beginning and throughout the three-year study period. The CYP2E1 protein is known to metabolize substrates, including pesticides, the exposure of which has been previously connected to the development of Parkinson’s disease, according to Gonzalez-Latapi.  

“It’s a significant step towards unraveling the complex interactions at play in Parkinson’s disease and could pave the way for pinpointing potential biomarkers for early detection and progression,” Gonzalez-Latapi said. 

“The characterization of DNA methylation and gene expression patterns in blood holds the potential to help us understand complex interactions between environmental and genetic factors in development of Parkinson’s disease. From a broader perspective, such patient-based studies will help categorize Parkinson’s disease patients through a biological lens that will ultimately facilitate the development of more precise treatments for patients with different subtypes of disease,” said Dimitri Krainc MD, PhD , the Aaron Montgomery Ward Professor and chair of the Ken and Ruth Davee Department of Neurology, who was senior author of the study.  

Moving forward, Gonzalez-Latapi said her team aims to study DNA methylation data from patients who are in the prodromal phase of Parkinson’s — those who are at risk of developing the disease but are not yet symptomatic. They also hope to study how environmental exposures, such as pesticide exposure, impact methylation changes in patients over time, she added.  

Co-authors of the study include Bernabe Ignacio Bustos, PhD, a postdoctoral fellow in the Krainc laboratory; Siyuan Dong, MS, a statistical analyst with the Biostatistics Collaboration Center ; Steven Lubbe, PhD, assistant professor in the Ken and Ruth Davee Department of Neurology’s Division of Movement Disorders; and Tanya Simuni, MD , the Arthur C. Nielsen, Jr., Research Professor of Parkinson’s Disease and Movement Disorders and director of the Parkinson’s Disease and Movement Disorders Center.  

PPMI is funded by the Michael J. Fox Foundation for Parkinson’s Research and funding partners. This work was also supported by a PPMI Early Investigator Award.  

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A 'radically different' way of looking at Parkinson's disease

by University Health Network

An international research team led by Krembil Brain Institute Neurologist and Senior Scientist, Dr. Anthony Lang, has proposed a new model for classifying Parkinson's disease (PD).

In recent decades, researchers have uncovered several biological factors that underlie PD. Key factors include a build-up of the protein α-synuclein in the brain, which leads to neuron degeneration, and genetic factors that increase one's risk of developing the disease. They have also begun to develop reliable methods to test for these factors, called biomarkers, in living patients.

Despite these advancements, doctors still diagnose the disease based on clinical features, such as the presence of tremors and other common motor symptoms.

According to Dr. Lang, who is the Lily Safra Chair in Movement Disorders at the University Health Network (UHN) and the Jack Clark Chair for Parkinson's Disease Research and a Professor in the Department of Medicine, at the University of Toronto, this traditional approach to diagnosing PD does not account for the complex biological processes at play.

"We know Parkinson's exists in the brain for one to two decades, or longer, before the clinical manifestations present," says Dr. Lang. "So, we believe current research must be driven by biological determinants of the disease, rather than limited clinical descriptions of its signs and symptoms."

He adds, "We need a radically different way of looking at this disease."

In a recent article published in Lancet Neurology , Dr. Lang's team proposed a new, biologically based model for classifying PD, called SynNeurGe (pronounced "synergy").

The model emphasizes the important interactions between three biological factors that contribute to the disease:

• the presence of pathologic α-synuclein in the brain (S);
• evidence of neurodegeneration, which occurs as the disease progresses (N); and
• the presence of gene variants that cause or strongly predispose a person to the disease (G).

According to the team, this "S-N-G" classification system better accounts for the biological heterogeneity of PD and the many ways the condition can present in patients. Consequently, the system could help researchers identify subgroups of patients that have distinct disease processes and develop clinically meaningful disease-modifying therapies.

"We need to recognize that Parkinson's can differ dramatically between patients. We are not dealing with a single disorder," explains Dr. Lang. "Our model provides a much broader, more holistic view of the disease and its causes."

"With this new model, Dr. Lang is spearheading a truly pivotal international effort to redefine the biological complexity of Parkinson's Disease, which will lead to more advanced and streamlined research in this area, and ultimately, to precision medicine for patients," says Dr. Jaideep Bains, co-Director of UHN's Krembil Brain Institute.

The team is confident that this new way of looking at PD will help researchers study its molecular basis , distinguish it from other neurodegenerative conditions that share common biological features, and identify targets for new therapies.

Despite these potential applications, Dr. Lang cautions that the model is intended for research purposes only and is not ready for immediate application in the clinic. Yet, it is already spurring hope among patients and the medical community.

"The ability to tailor treatments improves when you can identify exactly what is going on in a specific patient like me," says Hugh Johnston, Founding Chair of The Movement Disorders Patient Advisory Board at UHN's Krembil Brain Institute, who is currently living with PD. "This new way of thinking is what we have been waiting for. It's a game changer."

"Without looking at the biology, you can't get answers. And without answers, we won't have much-needed breakthroughs in Parkinson's," says Dr. Lang. "This new classification system and the future research project it will inspire, is one of the most exciting things I have worked on in my career."

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New research challenges conventional picture of Parkinson's disease

A new study highlights the role of misfolded tau proteins in the genesis and trajectory of Parkinson's disease. Graphic by Jason Drees/ASU

Parkinson's disease, the second most common type of progressive dementia after Alzheimer's disease, affects nearly 1 million people in the U.S. and an estimated 10 million individuals worldwide. Each year, close to 90,000 new cases of Parkinson’s disease are diagnosed in the U.S.

In a new study, Jeffrey Kordower , director of the ASU-Banner Neurodegenerative Disease Research Center , and his colleagues unveil pivotal insights into the progression of Parkinson's disease, presenting new hope for patients battling the severely debilitating disorder.

The research highlights the role of a critical protein called tau in the early stages of the disease. The results suggest that aggregates of the tau protein may jump-start processes of neuronal damage and death characteristics of the disease.

The findings challenge the conventional view of Parkinson’s disease pathology, which typically focuses on the protein alpha-synuclein as the classic diagnostic hallmark of the disease. The new study illustrates how tau pathology could be actively involved in the degeneration of dopamine-producing neurons in the brain, independent of alpha-synuclein. This revelation could shift the focus of Parkinson’s disease research, diagnosis and treatment.

“Currently, a protein called alpha-synuclein is believed to be the main player in Parkinson’s disease pathogenesis,” says Kordower, who is also a professor with ASU’s School of Life Sciences . “This study highlights that misfolded tau may be the first player in causing the cardinal motor symptoms in the disease.”

The study appears in the current issue of the journal Brain .

Shattering progression

The progression of Parkinson’s disease involves distinct stages, and the timeline can vary significantly among individuals. The typical stages of Parkinson's, as outlined by the Parkinson's Foundation , can help patients understand the changes as they occur.

The disease impacts people in different ways, and not everyone will experience all the symptoms or experience them in the same order or intensity. Some may experience the changes over 20 years or more; for others, the disease advances rapidly.

The progression of the disease is influenced by a combination of genetic and environmental factors. Following a diagnosis, many individuals experience a good response to medications such as levodopa, and this optimal time frame can last for many years.  Over time, however, modifications to medication are often needed and symptoms may intensify.

The prevalence of Parkinson’s has doubled in the past 25 years, which may be related to population growth, aging, genetic predisposition, lifestyle changes and environmental pollution.

A fresh perspective

The tau protein accumulates in two regions: the substantia nigra and putamen, both part of the basal ganglia in the brain. The substantia nigra is responsible for the production of dopamine, which is critical for modulating movement, cognitive executive functions and emotional limbic activity.

The putamen, a component of the dorsal striatum, is involved in movement initiation, selection and decision-making, as well as learning, memory, language and emotion. Dysfunction in the putamen can contribute to various disorders, particularly those related to motor function.

A wide range of physical and mental symptoms characterize Parkinson’s disease. These include: rhythmic tremors, often beginning in a limb, such as the hand or fingers; slowness of movement, which can lead to difficulty in performing simple tasks; muscle stiffness or rigidity; and difficulties with balance.

In addition to these physical symptoms, Parkinson's disease can also cause various mental and emotional changes, including depression and anxiety, sleep disorders, memory difficulties, fatigue and emotional changes.

Brain traces of disease

The scientists conducted the study using postmortem brain tissue from older adults who had experienced different degrees of motor impairment. The research analyzed brain tissues from individuals with no motor deficits, mild motor deficits with and without Lewy pathology in the nigral region of the brain, and from individuals clinically diagnosed with Parkinson's disease.

Lewy bodies are abnormal aggregates of the protein alpha-synuclein that accumulate in the brain, and they are a hallmark of several neurodegenerative disorders, including Parkinson’s and dementia with Lewy bodies.

In the case of Parkinson’s, Lewy bodies are primarily found in the substantia nigra, a region of the brain that is crucial for movement control, which leads to characteristic motor symptoms such as rigidity, tremors and bradykinesia (slow movement).

The study focused on a cohort of subjects with mild motor impairments — not pronounced enough to diagnose Parkinson’s, but still significant. Dividing these subjects based on the presence or absence of α-synuclein, researchers found that tau pathology was a common denominator.  

The researchers observed that the brain tissue associated with minimal motor deficit demonstrated similar accumulations of tau to those with advanced Parkinson’s, suggesting that tau's role occurs early in the disease's evolution. These findings open doors to earlier diagnosis and intervention, potentially slowing or altering the disease's progression.

The research also sheds light on parkinsonism, a condition that mimics Parkinson’s disease symptoms but is distinct in its underlying mechanisms. The study suggests that tau pathology in the nigrostriatal region of the brain is a shared characteristic, offering a new lens through which to view and treat various forms of parkinsonism.

The findings also underscore the potential of targeting tau pathology as a therapeutic approach in Parkinson’s disease. Because tau aggregation correlates with motor deficits and degeneration of dopamine-producing regions of the brain, interventions aimed at reducing tau accumulation could offer new hope for altering the disease's trajectory.

Kordower is joined by researchers from Neurodegenerative Diseases Research Unit, Biogen, Cambridge, Massachusetts; Aligning Science Across Parkinson’s (ASAP) Collaborative Research Network, Chevy Chase, Maryland; Neurology, School of Medicine, Georgetown University Medical Center, Washington, D.C.; Department of Neurology, University of Alabama at Birmingham; and Pacific Parkinson’s Research Centre and Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver.

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AUDIO : New breakthrough in research of Parkinson's disease

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Australian researchers in Melbourne investigating the cause of Parkinson's disease have made a breakthrough bringing hopes of new, faster treatments.

A team of scientists from the Walter and Eliza Hall Institute of Medical Research studied how a key protein causes the disease.

Professor David Komander led the research discovery, he spoke with ABC NewsRadio's Scott Wales.

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What You Need to Know about the New Parkinson’s Biomarker

A recent study in the journal Lancet Neurology announced the discovery of new biomarker for Parkinson’s disease.  The assay, which targets a protein found in the nervous system called alpha synuclein, can detect the disease in both people with Parkinson’s and individuals not yet diagnosed or exhibiting symptoms of the disease, but who are at a high risk of developing it. 

The discovery emerged from the Parkinson’s Progression Markers Initiative (PPMI), a decade-long longitudinal study led by the Michael J. Fox Foundation for Parkinson’s Research (MJFF) with support from more than 40 other organizations. More than 1,400 participants, both with and without Parkinson’s, participated in the PPMI study.  

Irene Richard, MD , a professor of Neurology and Psychiatry at the University of Rochester Medical Center (URMC), was involved in the development and planning of the PPMI study in her role as senior medical advisor to MJFF, a position she held from 2008-2011.  Richard continued her work with the organization as a member of the scientific advisory committee and was the principal investigator for the Rochester site of the PPMI study, overseeing the enrollment, evaluations, and follow up the initial cohort of study participants. We asked Richard why this new finding is important and what it means for future research efforts.

Describe alpha synuclein and the role it plays in Parkinson’s disease.

Abnormalities in alpha synuclein, a protein normally found in the nervous system, is associated with damage to neurons. Aggregates of misfolded and clumping of alpha synuclein that accumulate in the nervous system have been considered a hallmark of Parkinson’s disease (PD), but until now have only been detectable post-mortem. This new assay enables the detection of abnormal alpha synuclein during a patient’s life–and years before the clinical features of the PD appear. 

While the assay was remarkably good at detecting PD pathology and doing it at very early stages, it did not pick up abnormal alpha synuclein in some patients with PD, mainly those with certain genetic forms of the disease. This provides support for the notion that there may be “subtypes” of PD that, while manifesting the same signs and symptoms, likely have differing underlying pathophysiology.  This aspect will facilitate the development of targeted therapies and precision medicine approaches.

Why is it important to diagnose Parkinson’s early?

To date, we have only been able to treat the symptoms of the disease. Since PD is a progressive, neurodegenerative disease, a major goal has been to develop an intervention that could slow, or even stop progression.  The sooner in the disease course one could do that, the better off the patient would be.  Of course, the “holy grail” would be to actually prevent the disease from taking hold in the first place. 

Traditionally, PD is diagnosed when patients develop the characteristic motor symptoms such as tremor and slowness.  However, we have learned that the disease process has already begun long before these motor symptoms even manifest. For example, we now know that patients may have what we refer to as “pre-motor” symptoms such as diminished sense of smell, constipation, and a sleep disturbance known as “REM behavior disorder” wherein patients act out their dreams.

It is likely that, even if an intervention that was able to slow disease progression was developed, by the time someone has motor symptoms it may be too late.  The disease process has silently been causing neuronal loss for years, the “horse is already out of the barn,” and saving the limited number of neurons left may not suffice.  In the event we discover a disease modifying intervention, the earlier it can be given, the more likely it is to be effective–which is why there has been such a push to find ways to detect the disease at its earliest stages.

What more needs to be done before this is widely used to screen for Parkinson’s disease? 

This is a first step, but it is a big one–think Neil Armstrong.  At this point, the assay has been used on spinal fluid, obtained through a lumbar puncture or “spinal tap”.  However, it seems only a matter of time before further developments and refinement will enable it to be performed on fluids more readily accessible, such as blood, saliva, nasal secretions or potentially using a skin biopsy. 

How will this discovery help advance new treatments?

This assay will enable us to establish objective endpoints for clinical trials of PD treatments, ensure study participants exhibit appropriate pathology, and detect therapy induced changes in their status.  All of these factors will significantly decrease the risk to industry to invest in the development of potential “blockbuster” therapies, including preventative agents, and increase the speed with which they can be developed, tested, and brought to market.

One of the great challenges has been to find a way to actually measure disease progression.  To date, we have relied on clinical measurements, using a standardized rating scale, which while validated is far from an ideal objective measure of progression.  This is, in part, because one of the rather unique aspects of the disease is that the clinical features vary among and within patients, are affected by symptomatic medications, and can fluctuate, even within the course of a day. 

We knew that we must find an objective way to measure disease progression in parallel with seeking an intervention that could modify it.  A lack of such a measure has resulted numerous clinical trials yielding results that were difficult to interpret.  Complex clinical trial designs were a step forward, but have not been able to compensate for the lack of an objective and reliable biomarker.  This assay represents a big step forward in meeting that need.

What does this discovery mean to the Parkinson’s research community?

I have spent my entire academic career at the University of Rochester and have focused on PD, both clinical care of patients and clinical research.  To witness the growth and be part of this worldwide effort has been inspiring and I am thrilled with this breakthrough. There is a unique sense of energy and commitment that comes from being part of something greater than ourselves—a collective desire by everyone involved to alleviate the suffering of those living with PD now, with the hope of a future in which the disease will be a thing of the past.  

For more information: Michael J. Fox Foundation for Parkinson’s Research–Breaking News: Parkinson's Disease Biomarker Found

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New therapeutic target for Parkinson's disease discovered

Restoring contacts between mitochondria and lysosomes improves neuronal function.

Northwestern Medicine scientists have uncovered a new mechanism by which mutations in a gene parkin contribute to familial forms of Parkinson's disease. The discovery opens a new avenue for Parkinson's therapeutics, scientists report in a new study.

The Northwestern scientists discovered that mutations in parkin result in a breakdown of contacts between two key workers in the cell -- lysosomes and mitochondria.

Mitochondria are the main producers of energy in cells, and lysosomes recycle cellular debris that accumulates during normal function of our cells. These organelles are especially important in our brains because neurons are highly dependent on energy production by mitochondria, and because of their activity, neurons produce an abundance of cellular debris that must be cleared by lysosomes.

In a prior study, published in Nature, Dr. Dimitri Krainc, chair of neurology and director of Simpson Querrey Center for Neurogenetics at Northwestern University Feinberg School of Medicine, and his group discovered that lysosomes and mitochondria form contacts with each other. After the initial discovery, Northwestern scientists tried to understand the function of these contacts in Parkinson's disease.

In the new study published in Science Advances, the investigators report that lysosomes help mitochondria by providing key metabolites for their function. Mitochondria must import many of their essential ingredients, but it has not been well known where some of these metabolites come from. On the other hand, lysosomes serve as recycling factories in cells and, therefore, produce many breakdown products that could be used by other organelles such as mitochondria.

In this work, scientists found that lysosomes provide important amino acids that support the function of mitochondria. However, they also found that in some forms of Parkinson's disease, lysosomes cannot serve as a "helping hand" to mitochondria because the contacts between the two organelles are disrupted. This results in dysfunctional mitochondria and ultimately degeneration of vulnerable neurons in Parkinson's disease.

"Findings from this study suggest that dysregulation of mitochondria-lysosome contacts contributes to the Parkinson's disease pathophysiology," said Krainc, the study's corresponding author. "We propose that restoring such mitochondria-lysosome contacts represents an important new therapeutic opportunity for Parkinson's disease."

From a broader perspective, this study opens a new avenue of research in neurodegenerative disorders, by highlighting the importance of direct communication and collaboration between cellular organelles in the pathogenesis of these disorders.

The first author of the study is Dr. Wesley Peng who recently completed the medical scientist training program (MD-PhD) at Northwestern and currently serves as a neurology resident at Mass General Brigham and Harvard Medical School. Other contributors to the study include Leonie Schroder, Pingping Song and Yvette Wong.

The study was supported by the following National Institute on Aging grant AG066333, National Institute of Neurological Disorders and Stroke (NINDS) grants NS109252 and NS122257, all from the National Institutes of Health.

• Parkinson's Research
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Story Source:

Materials provided by Northwestern University . Note: Content may be edited for style and length.

Journal Reference :

• Wesley Peng, Leonie F. Schröder, Pingping Song, Yvette C. Wong, Dimitri Krainc. Parkin regulates amino acid homeostasis at mitochondria-lysosome (M/L) contact sites in Parkinson’s disease . Science Advances , 2023; 9 (29) DOI: 10.1126/sciadv.adh3347

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What’s New in Parkinson’s: November 2023

This month's "What's New in Parkinson's" post features a surprising study about alpha-synuclein and tau as factors in Parkinson's pathophysiology, multiple articles describing nuances of deep brain stimulation, and stories about exceptional athletes living with Parkinson's.

Read on for all of November's Parkinson's news!

SCIENCE AND RESEARCH Updates

• Chu et al. found dopaminergic neurodegeneration can independently occur of alpha-synuclein aggregation. They claim that tau--a protein more commonly associated with Alzheimer's--is involved in early stages of Parkinson's-related neurodegeneration . These findings are "striking," because alpha-synuclein has long been thought to be the more significant driver of Parkinson's pathology.
• An article in  NPJ  highlights the potential of smartphones and wearable technology to help research and manage multiple conditions--including Parkinson's. The article highlights cost, accessibility, and safeguarding health data as areas of concern.
• Hanff et al. discuss sex-specific differences in Parkinson's . Women living with Parkinson's were observed to have slower progression of cognitive issues, apathy, and sleep disturbances. Women with Parkinson's also have significantly worse scores for depression and pain at diagnosis. Depression and bodily discomfort were the only two symptoms examined that progressed faster for women than for men.
• Risk factors commonly associated with increased incidence of obstructive sleep apnea include older age, male sex, and higher BMI. In a new study of 1448 people living with Parkinson's, 45% of participants experienced sleep apnea. In addition to the general risk factors, for people experiencing Parkinson's, more severe motor symptoms, dopamine agonist use, and more prevalent daytime sleepiness were associated with risk of sleep apnea. Early detection is an aspect of improving health outcomes for people living with Parkinson's and obstructive sleep apnea.
• In an animal model of Parkinson's, researchers found that a high-sugar diet did not induce neurodegeneration and protected from induced neurodegeneration caused by the neurotoxin 6-OHDA, which is commonly used to induce neurodegneration in animal studies. But don't go stocking up on ice cream: Although this research involved non-human animals, the research found decreases in life-span are associated with a high-sugar diet.
• Gene therapy targeting the brain's dopamine system reversed symptoms of Parkinson's without dyskinesia in primate research.
• A team of palliative care experts explored benefits of educating general neurologists about palliative care for people with Parkinson's . The benefits were minor, but the team sees opportunities to improve the education provided and the interventions recommended.
• Henrich et al. discuss the role of mitochondria in Parkinson's.
• Bifidobacteria can feed on levodopa. Cirstea et al. found there is an association between high levels of bifidobacteria and high doses of levodopa . They offer two possible explanations for the association. People with higher levels of bifidobacterium require a higher dose of levodopa because their gut bacteria consumes part of each dose. Additionally, people who require higher doses of levodopa support a large volume of bifidobacterium which uses residual L-DOPA for metabolic purposes. Over-interpreting this research would be a mistake, Cirstea et al. cite the low efficiency of bacteria in consuming levodopa and that other digestive disturbances are likely more influential on metabolism of levodopa.
• By evaluating voice recordings, AI technology differentiates people with Parkinson's from people without Parkinson's.
• Three Parkinson's experts describe why they believe genetics are rarely sufficient to explain the onset of Parkinson's.
• A new Parkinson's research center is being formed at Yale University.

TREATMENT and Therapy Updates

• Marc Gauthier from Bordeaux, France, who lives with advanced Parkinson's, received a spinal implant that dramatically improved his walking ability. The device was implanted as a part of early stage research ; six more people with Parkinson's will soon receive similar devices. Researchers note that deep brain stimulation (DBS) may have similar effects, but in the future, the spinal implant may be an alternative for people who are not good candidates for DBS.
• Genetic subtyping of people with Parkinson's may help predict efficacy of DBS. Pal et al. discuss the controversies and gaps in knowledge surrounding risks of subthalamic DBS for people who carry certain GBA gene variants.
• In a letter to the editor of  Brain Stimulation , Sasikumar et al. report on a small study that used DBS to provide intermittent stimulation to a part of the brain called the nucleus basalis of Meynert. Intermittent stimulation improved sustained attention, while continuous stimulation had no affect on cognition. This may support previous findings in primate research; there are implications of the research regarding gait.
• In Movement Disorders, Boogers and Fasano describe differences between DBS targeting the subthalamic nucleus and DBS targeting the globus pallidus internus . The former can have more profound positive outcomes as well as more complicated detrimental effects than the latter.
• Impulse control disorders and apathy are major challenges for many people with Parkinson's. Theis et al. find there may be genetic risk factors for these symptoms.
• "First Steps" is a peer-led, self-management intervention for people newly diagnosed with Parkinson's in the UK. The primary positive effect of the program is the likelihood of increased physical activity. Other possible positive effects included benefits to mental health and decreases in care partner strain.
• Asano et al. compare the safety of rasagiline, safinamide, and selegiline : three MAO-B inhibitors used to treat Parkinson's. REM sleep behavior disorder is not associated with safinamide, but is associated with rasagiline and selegiline. This may be due to safinamide's influence on glutamine--an influence that the other MAO inhibitors do not share.

LIVING WELL STORIES

• Golfer John Senden plans to keep professionally playing despite a recent Parkinson's diagnosis. He says, "I've got to stay in the gym, stay fit and stay open, because Parkinson's wants to close you down [...] It's not going to go away, but I'm still able to play and still enjoying golf."
• Rolling Stone shares the story of renowned mixed martial artist Rickson Gracie's unstoppable energy while living with Parkinson's.
• Randy Bryson was diagnosed with Parkinson's in 2012 and started Parkinson's Artisans to help people with Parkinson's share the benefits he found from participating in creative arts .
• Diagnosed with Parkinson's amidst a successful career, Bill Brown has lived with Parkinson's for nearly 10 years. He is committed to family and fundraising, and inspires his sons as they pursue their dream of being olympic athletes.
• USA Today features the story of Sara Whittingham , a physician diagnosed with Parkinson's three years ago and competed in a 140-mile triathlon.

SURVEYS, CLINICAL TRIALS, AND VOLUNTEER OPPORTUNITIES

• Researchers in the UK and Australia began recruiting participants for a trial aiming to prevent people with REM sleep behavior disorder from developing Parkinson's by reducing inflammation.
• Researchers in Sweden will begin recruiting participants for a trial of montelukast versafilm : a drug used to treat asthma and allergies. The research will explore whether montelukast has any neuroprotective effect .
• Texas Tech in Lubbock, Texas is undertaking a study about the effects of Parkinson's on family functioning .
• Researchers in Holland are enrolling participants in a trial evaluating the use of motivational smartphone apps to increase exercise program adherence.
• Inhibikase is recruiting participants for a phase 2 trial of a new c-Abl tyrosine kinase inhibitor. In a press release , Inhibikase says their research "has validated the critical role that c-Abl plays in the initiation and progression of Parkinson's disease, as well as the potential of IkT-148009 as a promising new approach to disease modification." This trial is among the first to utilize recently validated alpha-synuclein seed assay tests.
• The International Parkinson and Movement Disorders Society (MDS) is developing a new electronic diary (e-Diary): a digital solution for Parkinson's. This e-Diary is intended to better characterize how the disease affects daily life. The MDS invites people to participate in a survey to help aid the design of this new tool .
• A new trial studying Gemfibrozil , a drug that decreases fat production in the liver, is set for a phase two clinical trial in people with Parkinson's. This trial will enroll people between 40 and 75 years of age who have not begun taking medication for Parkinson's.
• The Speech Accessibility Project (SAP) seeks volunteers for a research initiative aiming to make voice recognition technology more useful for people with diverse speech patterns. More information is available here and here . To determine whether you are eligible to participate, visit the SAP registration page .
• A team of Dutch researchers created PregSpark, a registry for women with Parkinson's who are pregnant or have recently given birth. The goal is to build an online international pregnancy and Parkinson’s registry. This registry will prospectively and uniformly collect data on the course and outcome of as many as possible pregnancies in women with Parkinson’s. This data will help women with Parkinson's make informed decisions about pregnancy and improve the quality of care pregnant women with Parkinson's receive. The PregSpark site is currently under construction but should be completed soon.
• A phase 1b trial is recruiting volunteers for a study of a treatment aiming to influence inflammation .
• Researchers in Norway are investigating the efficacy of ambroxol in people with dementia with Lewy bodies.
• Researchers in the UK, in partnership with the Women's Parkinson's Project and MyMovesMatter , invite participation in a survey about the experience of menopause for women with Parkinson's.
• Another study of ambroxol is launching: The DUPARG study is recruiting participants in Groningen, Netherlands.
• A new trial examining the possible neuroprotective effect of exercise has been listed by the University of Nevada.
• University of Rochester Center for Health + Technology is undertaking a survey study to assess the ability of the Parkinson’s Disease-Health Index to measure patient-relevant changes in disease burden over the course of two years. Participants will complete surveys five times over two years and must be over 18, speak English, and have a self-reported or clinical diagnosis of Parkinson’s. More information is available here .
• Researchers at Columbia University’s Irving Medical Center are seeking participants for a study exploring the role of immune response in Parkinson’s. Participation is open to those with and without Parkinson’s and will involve donating blood, a questionnaire, a cognitive test, and a neurological examination. Click here to express interest in participating.
• Johns Hopkins University has announced a trial to evaluate whether levetiracetam can improve symptoms of Parkinson's psychosis. The trial is not yet recruiting, but the plan is for it to begin by September. The trial design features a crossover assignment, which means every participant will receive an active trial drug for their participation.
• The LUMA trial continues to recruit participants. This trial aims to assess the safety and efficacy of BIIB122 tablets in slowing the progression of early-stage Parkinson’s. This study has sites in the US, China, France, Germany, the Netherlands, Poland, Spain, and the UK.
• The ACTIVATE trial is recruiting participants for a phase 2 trial of BIA 28-6156 in people with GBA mutations. This 78-week trial has site locations in the US, Canada, and Europe.
• In Colorado, a study the Foundation is funding continues to recruit participants. The study explores low-load resistance training with blood flow restriction to help develop exercise interventions for improved quality of life for people with advanced Parkinson’s.
• Washington University School of Medicine is sponsoring a study aiming to enroll participants with idiopathic REM sleep behavior disorder , as well as healthy controls, in preparation for a trial of neuroprotective treatments against synucleinopathies.
• A study in South Carolina hopes to identify brain biomarkers to predict the risk of cognitive change following DBS surgery.
• A survey in Ireland seeks to understand the influence of Parkinson’s symptoms and other factors on the quality of life .
• Another survey for those in Ireland seeks to understand how people access information about Parkinson's.
• A trial sponsored by the University of Aberdeen in Scotland is recruiting participants for a study of the effects of constipation and changes in the microbiota in Parkinson’s.
• Staying Connected through Communication Study : The University of Washington SPEAC Lab invites individuals living with Parkinson’s to answer survey questions about their communication experiences. This is an online survey study that will take about 30-45 minutes. (Paper surveys are also available.) People with Parkinson's and their family/friends/coworkers will complete SEPARATE surveys, and data are not shared between participants. This study is open to anyone in the US. Each participant will be mailed a $25 check upon survey completion.
• PreActive PD Study : This study, available for both English and Spanish speakers, implements an occupational-therapist-delivered physical activity behavior change coaching intervention in people with early-stage Parkinson's. The study is based upon a recent single-arm cohort feasibility study (Pre-Activate PD/HD) that evaluated acceptability, implementation, and resulting effect estimates of the Pre-Activate PD intervention in 13 participants. The intervention provides one-on-one coaching sessions from an occupational therapist to individuals newly diagnosed with Parkinson's. The individualized structured support in the sessions is aimed at facilitating and optimizing exercise uptake as part of an effective self-management program.
• Gamma Wave Trial : Sponsored by the Massachusetts Institute of Technology (MIT), this trial investigates the efficacy of a non-invasive method of neuromodulation called Gamma Entrainment Using Sensory Stimulation (GENUS) for managing Parkinson's motor symptoms. GENUS is administered via light, sound, and tactile stimulation devices and has been tested on cognitively normal individuals and individuals with mild Alzheimer's; the device was found to be safe for use and effective for entrainment in both populations.
• Deep Brain Stimulation (DBS) and Exercise Study at Barrow Neurological Institute: This study aims to help researchers learn more about how aerobic exercise affects symptoms of Parkinson’s and the quality of life in people who have DBS. They will also look at brain wave activity using the Medtronic Percept DBS device to better understand what changes in the brain might be caused by exercise and how that affects Parkinson's symptoms. Phoenix-area residents reach out to Markey if interested.
• Colorado Oral Strengthening Device : The University of Colorado Denver is looking for adults with Parkinson's to participate in a study exploring how a novel low-technology device can increase tongue strength comparable to standard-of-care exercise using tongue depressors but with the kinematics and simple biofeedback of existing high-cost devices . Research has shown that tongue resistance exercises paired with biofeedback result in improved tongue strength to support chewing, control of food and liquid in the mouth,  and propulsion of material for a swallow.
• PD GENEration : The Parkinson’s Foundation announces a major expansion of its national study to make genetic testing and counseling more available for people with Parkinson’s. The study ( NCT04057794 ) hopes to enroll 15,000 people in all 50 US states, Puerto Rico, and the Dominican Republic. For questions about enrollment, email [email protected] . Know someone who speaks Spanish and wants to learn more and maybe participate in the study? Share this link .
• Parkinson’s Progression Markers Initiative : In an expanded study, the Parkinson’s Progression Markers Initiative (PPMI) is currently working to enroll up to 100,000 people with and without Parkinson’s. The study team is especially seeking to enroll people diagnosed with Parkinson’s in the past two years and who are not yet on treatment, as well as people 60 and older who aren't living with Parkinson’s but have a risk factor for it (such as a close relative with Parkinson’s, a known Parkinson’s-associated mutation, and/or REM sleep behavior disorder). The observational study is also enrolling people with no known connection to Parkinson’s to serve as a control group.
• TOPAZ  (T rial   of   Parkinson’s   and   Zoledronic Acid): Caroline Tanner, MD, PhD, is recruiting participants for a new remote clinical trial led by a team of Parkinson’s experts at UCSF in partnership with researchers from across the country. The study aims to help people with Parkinson’s or parkinsonism maintain their independence by reducing the risk of hip fractures. The study will test if zoledronate,   an   FDA-approved medication for osteoporosis, can prevent fractures in people with Parkinson’s--whether or not they have osteoporosis. To learn more, visit the study website at TOPAZstudy.org , email [email protected] , or call (415) 317-5748.
• A PD Avengers research group is undertaking a new project called Sparks of Experience, designed to be more systematic about collecting and considering the experiences and ideas that come from the curious minds of people living with Parkinson’s. "In the past, these sometimes quirky ideas inspired by lived experience have turned into significant new directions for research. It could be said we are trying to capture serendipity," the team says. To learn more and get involved, see the flyer here . 
• Game-Based Exercise Project: Researchers at the University of Auckland are investigating how games can be used as potential rehabilitation systems. This project aims to develop suitable game-based exercise experiences to help people living with Parkinson's. If you are 45 or older, living with a chronic condition such as Parkinson's, and/or are experiencing age-related health conditions, you are invited to participate in a survey that will help the researchers to understand the community's interest in games and gameplay in the context of exercise and rehabilitation. To learn more and take the 15-minute survey, see the flyer here . 
• SPARX3 - A Phase 3 Clinical Trial about Exercise and Parkinson's: This research team is currently seeking volunteers to participate in a clinical trial about the effects of aerobic exercise on people with Parkinson’s. Learn more and see if you qualify here . For more details, contact Katherine Balfany at [email protected] .
• The University of Oulu and collaborators from Aalborg University, Fraunhofer University, the University of Manchester, the University of Glasgow, the University of Lisbon, and the University of Melbourne are conducting a survey for people with Parkinson's and care partners about self-care. Complete the survey here to share your self-care strategies and techniques. You can also review ideas submitted by others and add them to your own self-care toolbox.
• Speech and Telemedicine Study : The Purdue Motor Speech Lab
• Parkinson’s and Service Dogs : University of Groningen, Netherlands
• Neurology Study Interest Registry : University of Rochester

For more of what's new in Parkinson's news, check out our full series here . 

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• New partnership aims to boost genetic research in Parkinson’s

Parkinson's Foundation teams up with Tasso to get patient blood samples

by Patricia Inácio, PhD | April 26, 2024

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The Parkinson’s Foundation has joined forces with Tasso — a U.S. company that offers a sample collection and logistics platform for clinical trials — to accelerate genetic research into the underpinnings of Parkinson’s disease .

The collaboration will harness Tasso’s patient-friendly blood collection technology to acquire small blood samples as part of PD GENEration , a large study offering Parkinson’s patients free genetic testing, along with genetic counseling to help them understand the results.  

That study (NCT04057794 ), which was launched in 2019, tests for mutations in selected clinically relevant genes for Parkinson’s disease. Data are analyzed in real-time by the  Parkinson’s Disease Gene Curation Expert Panel , which encompasses geneticists, neurologists, and genetic advisors who examine the collected information and select potential clinically relevant genes for further research and therapy development.

“The data shared from PD GENEration will drive scientific research forward and improve the understanding of Parkinson’s disease,” James Beck, PhD, senior vice president and chief scientific officer at the Parkinson’s Foundation, said in a press release .

“With Tasso as our partner, we now have a viable platform to enable our ambitious goal of whole-genome sequencing, which offers a promising pathway to better understand the genetics of PD [Parkinson’s disease] and to facilitate research toward new therapies for PD,” Beck said.

The data also will allow researchers to identify which patients are eligible for clinical trials, which could accelerate research and improve care, according to the partners.

PD GENEration Now Includes 20+ Clinical Sites, Aims to Enroll 15,000

Partners will use pd generation study to advance genetic research.

Participants in the PD GENEration study now are receiving a kit with Tasso’s blood collection device, for use in the comfort of their homes. The company’s patented technology assures a painless blood sample collection, designed to make it easy for participants or their care partners to complete the process.

The blood collection and its successful completion are supervised by online doctors. Once completed, patients ship their samples in a pre-paid box for analysis in an accredited laboratory.

The samples are then screened for mutations among genes known to play a role in Parkinson’s.

“Tasso and the Parkinson’s Foundation share a mission to accelerate life-changing research,” said Ben Casavant, PhD, CEO and co-founder of Tasso.

“Ensuring study participation is accessible and approachable for PD patients is critical to success. We are proud to partner with the Parkinson’s Foundation to enable a better research experience for people living with PD,” Casavant added.

The PD GENEration study is sponsored by the Parkinson’s Foundation, along with the Global Parkinson’s Genetics Program (GP2). It’s part of the  Aligning Science Across Parkinson’s initiative , which is aimed at fostering collaboration and resources to understand the underlying causes of Parkinson’s.

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