Levodopa-Sparing Medications May Help Patients in Early Stages of Parkinson’s, Study Suggests

Early stage Parkinson's, Levodopa-Sparing Medications

Neurologists treating patients with early-stage Parkinson’s disease should prescribe more often therapies that spare patients from starting levodopa too soon in order to delay onset of side effects associated with long-term use of the medicine, findings from a study conducted in Romania suggest.

Researchers believe that even if a doctor believes a patient’s clinical situation required management with levodopa, they should first try to combine it with other antiparkinsonian therapies — such as other dopamine agonists or monoamine oxidase B inhibitors — in order to allow lower levodopa doses.

These findings resulted from a study, “Therapeutic strategies in the early stages of Parkinson’s disease: a cross-sectional evaluation of 15 years’ experience with a large cohort of Romanian patients,” which was published in the journal Neuropsychiatric Disease and Treatment.

Currently, the most effective and cost-saving therapy for lessening Parkinson’s symptoms is substitution therapy with levodopa. However, a major drawback of this therapy is the side effects associated with its long-term use.

After four to six years of treatment with levodopa, many patients may start experiencing spontaneous involuntary movements (dyskinesia), with some patients also having impulsive and compulsive behaviors. Its effectiveness can also reduce over time, causing patients to experience wearing-off effects, meaning that the therapy loses its ability to effectively manage Parkinson’s symptoms before it is time for the next dose.

Some clinical evidence seems to indicate that in many cases “if the therapy is started too early and with high doses, these complications may appear earlier and can be more severe, especially in younger patients,” the researchers wrote. This leads clinicians to try to avoid these side effects and adverse reactions by limiting levodopa doses as much as possible.

Based on clinical efficacy data from newer antiparkinsonian therapies in younger patients (under 60 years), European guidelines propose the use of levodopa-sparing medications as a first option for early-stage patients to delay the onset of motor and non-motor complications. But there is little real-world data to confirm how these therapeutic recommendations are being applied in clinical practice.

Therefore, the researchers reviewed the medical records of patients with early-stage Parkinson’s hospitalized between 2003 and 2017 at Târgu Mures Emergency County Hospital, in Romania, to gather real-world data on the use of levodopa and alternative therapies.

During this 15-year period, a total of 2,379 patients with Parkinson’s were hospitalized, of whom 1,237 had received the diagnosis for five years or less. The researchers justified this time window because most practicing neurologists consider that the efficacy of levodopa-sparing treatment strategies is significantly reduced after a five-year period. Only patients with early-stage disease were included in the study.

In this group, 18 patients (1.5%) were receiving monoamine oxidase-B inhibitors (MAO-Bi). A total of 665 patients were taking dopamine agonists, of whom 120 were taking the therapy alone (9.7%) and  83 patients (6.7%) in combination with MAO-Bi. Many of the patients (42%) were only taking levodopa, while 481 patients (38.8%) were taking levodopa in combination with other antiparkinsonian therapies.

Assessment of levodopa daily doses, either alone or in combination with other therapies, did not reveal any significant differences between patients grouped by age (younger than 50, 50–65, or older than 65).

“The therapeutic strategies used in the early stages of Parkinson’s disease in the study period are similar to those found in the literature,” the researchers wrote. Still, they recommend that “neurologists treating this disease should, with due diligence, apply a greater proportion of different levodopa-sparing combinations, especially if they are not financially burdensome.”

What makes clinicians decide to prescribe levodopa or other dopamine agonists in the first place is difficult to access through this study, and can be influenced by a number of factors, the researchers said.

“Because our study looks at a long period it is hard to retrospectively assess how much of the clinical decisions was influenced by the early optimism (as reflected in the initial studies) regarding the potential disease-modifying effect as well as the magnitude of the clinical efficacy of dopamine agonists,” they added.

Still, “if the severity of the clinical image requires substitution therapy, the use of combined therapies can significantly reduce levodopa doses and thus the requirement to use the minimum efficient levodopa dose can be achieved,” they concluded.

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Changes in Gait, Cognition May Be Early Signs of Idiopathic Parkinson’s, Research Suggests

gait and Parkinson's

Changes in gait and cognition precede a diagnosis of idiopathic (without known cause) Parkinson’s disease, and may occur earlier than typical non-motor symptoms, a study has found.

The study, “Prediagnostic markers of idiopathic Parkinson’s disease: Gait, visuospatial ability and executive function,” was published in Gait & Posture.

Motor symptoms in idiopathic Parkinson’s disease (IPD) are identified relatively late in the disease course, reducing the odds of neuroprotective benefit from available treatment options. Identifying individuals during the prodromal (early) period that precedes motor symptoms could be of great use for clinical studies seeking new therapies to prevent or delay disease progression.

A team of French researchers sought to determine the existence of any subtle gait disorders or other signs that precede the diagnosis of IPD, based on data from a long-standing study of human aging across the adult lifespan: the Baltimore Longitudinal Study of Aging (BLSA).

Conducted by the National Institute on Aging (NIA) Intramural Research Program, the BLSA continuously enrolls healthy volunteers age 20 and older who are followed throughout their life independently of the development of age-related diseases.

Ten pre-diagnosed IPD patients (eight men and two women) and 30 healthy control subjects were chosen for this study.

Subjects were assessed for the disease approximately 2.6 years before diagnosis. Clinical examination included gait speed, spatio-temporal gait parameters, balance, upper-limb motor skills, neuropsychological profile, and non-motor symptoms.

In comparison to the control group, IPD patients had shorter step length and reduced gait speed in a usual gait speed testing condition. Despite also having shorter step length when testing maximum gait speed, no differences between the IPD and control samples were found in walking speed.

Moreover, patients had worse mental rotation ability (the ability to rotate mental representations of two-dimensional and three-dimensional objects, which is related to the brain’s capacity for visual representation), and impaired ability to name different examples that could be inserted into a category (for instance, naming all types of flowers one can think of in one minute).

Compared to control subjects, IPD patients had no changes in upper-limb motor function, no depression, no sleep disturbances, no urinary symptoms, and no orthostatic hypotension (when blood pressure suddenly drops when standing up quickly).

Researchers concluded that the observed “changes might serve as markers to improve the early detection of IPD patients, who could then benefit from pharmacological neuroprotection trials and/or prevention trials of lifestyle-related interventions in order to delay, or even prevent, clinical manifestations.”

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Deterioration of Nerve Cell Structure Not the Main Cause of Early Parkinson’s Symptoms, Mouse Study Suggests

neuron structure changes

Although the structure of dopaminergic neurons gradually deteriorates before cell death, these alterations do not seem to account for the subtle impairments seen during the early stages of Parkinson’s disease, a mouse study has found.

The study, “Progressively Disrupted Somatodendritic Morphology in Dopamine Neurons in a Mouse Parkinson’s Model,” was published in Movement Disorders.

Parkinson’s is a progressive neurodegenerative disorder caused by the gradual loss of dopaminergic neurons in the substantia nigra, a region of the brain responsible for movement control.

Previous studies in animal models have shown that neuron dysfunction and cell death start to occur before animals display noticeable motor symptoms associated with Parkinson’s. However, the precise morphological (structural) and functional changes that occur in neurons at this early stage of disease are still not very well understood.

Researchers from the University of Texas Health used a mouse model of adult-onset parkinsonism that perfectly mirrors “the slow, progressive course of Parkinson’s seen in the majority of patients,” according to the study.

These mice, called MitoPark, lack the mitochondrial transcription factor A (TFAM) gene specifically in dopaminergic neurons. As a result, at 12 weeks of age, they show a marked decrease of brain innervation in the striatum — a region responsible for motor coordination — followed by neuron cell death at 30 weeks old.

To analyze the morphology of individual neurons in brain slices from MitoPark mice during the early stages of disease, researchers used a technique called whole-cell patch clamp — a technique that allows the study of the electrical properties of neurons — together with fluorescent labeling.

At 16 weeks of age, these animals’ dopaminergic neurons were significantly reduced in size with a lower number of branching points in dendrites — the long, slender projections of a neuron that carry an electrical signal from the cell body to the point of contact with another neuron, called the synapse.

“Alterations in somatic [cell body] and dendritic structure are likely to have direct effects on dopamine-dependent motor function and reward learning. In these neurons, dendrites serve important roles as sites for synaptic termination and contribute to many determinants of cell excitability,” the researchers said.

These defects worsened significantly as animals got older, from 16 to 31 weeks of age, eventually leading to neuronal death.

“Dendritic branching and soma size, although intact in dopamine neurons from 12-week-old MitoPark mice, are progressively and severely disrupted in a manner that undoubtedly impairs cellular function in advance of neuronal death,” the researchers wrote.

Although this decline in neuron morphology occurred at a similar rate in animals from both sexes, it did not begin until after the age at which the first mild locomotor and learning alterations start to occur (approximately 12 weeks).

As a result, the progressive and severe decline in neuronal morphology that occurs prior to cell death does not seem to be involved in the initial motor and cognitive impairments observed in this mouse model.

“This work could help identify the ideal time window for specific treatments to halt disease progression and avert debilitating motor deficits in Parkinson’s patients,” the researchers concluded.

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15 CSF Proteins Seen as Possible Biomarkers of Early Parkinson’s Fail at That Task, Study Reports

Parkinson's and biomarkers

Proteins in the cerebrospinal fluid that were seen as possible diagnostic biomarkers of Parkinson’s disease cannot serve in this role, because they lack robustness and reproducibility in earlier stages of the disease, a study has found.

The study, “Evaluation of cerebrospinal fluid proteins as potential biomarkers for early stage Parkinson’s disease diagnosis,” was published in PLOS One.

Parkinson’s is a chronic and progressive neurodegenerative disorder, mainly caused by the gradual loss of dopaminergic neurons in the substantia nigra, a region of the brain responsible for movement control. It is typically diagnosed based on the presence of motor symptoms, but these can be difficult to determine as disease-causing in Parkinson’s earlier stages.

Previous studies have suggested that specific proteins in the cerebrospinal fluid (CSF) —  which circulates in the brain and spinal cord — could work as early signals, or biomarkers, of disease to assist in a diagnosis. But CSF proteins have never been fully validated as Parkinson’s biomarkers in a clinical setting.

Researchers in Belgium, Germany, and the U.K. tested the suitability of 15 CSF proteins proposed as potential biomarkers for an early stage Parkinson’s diagnosis.

The panel of proteins explored were beta-amyloid (Aβ40 and Aβ42), alpha-synuclein (α-syn), tau (p-Tau and t-Tau),  neurofilament light chain (NFL), interleukin 6 (IL-6), protein deglycase (DJ-1), S100β (a calcium-binding protein), osteopontin (OPN), high-mobility group box 1 (HMGB1), ubiquitin carboxyl-terminal esterase L1 (UCHL1), Fms-related tyrosine kinase 3 ligand (FLT3LG), matrix metalloproteinase 2 (MMP2) and apolipoprotein A-I (ApoA1).

Researchers began by measuring the levels of these CSF proteins in a group of 80 patients with early stage disease and 80 healthy people serving as controls. Out of the 15 CSF proteins tested, six — α-syn, DJ-1, Aβ42, S100β, p-Tau and t-Tau — were significantly dysregulated among patients.

“Aβ42, t-Tau, p-Tau, α-syn and DJ-1 were decreased in early clinical PD [Parkinson’s disease] patients compared to the controls, whereas S100β levels was increased in early clinical PD patients,” the researchers wrote.

To confirm these candidates, researchers next performed this same test in an independent group of 30 Parkinson’s patients with advanced disease and 30 healthy controls. Here, a type of beta-amyloid, Aβ42, was the only CSF protein whose levels were significantly different — significantly lower — in Parkinson’s patients compared to controls.

“Decreased Aβ42 levels in CSF samples from PD patients had been reported recently, suggesting it may be a reliable candidate. However, in this study … analysis showed that this potential marker was not suitable for diagnostic purposes,” the researchers wrote.

Finally, to assess whether a combination of these markers could distinguish early Parkinson’s patients from healthy individuals, they used a machine learning approach based on an algorithm to identify markers that might improve disease diagnosis. Based on this model, a set of markers comprising α-syn, S100β, and UCHL1 were identified as promising candidates.

“[T]his model aligned with findings published in the literature, where α-syn is characterized as the hallmark protein of PD, closely involved in the progression of neuronal degeneration and subsequent motor impairments, while S100β has been considered a possible marker for the accompanying neurodegeneration,” the researchers wrote. However, “the decision tree could not be confirmed” in the second group of patients and controls.

“[C]urrently proposed protein CSF markers for PD diagnosis, as identified in late stage PD cohorts, lack robustness and reproducibility when applied in the early clinical stages of (…) PD,” they added.

The researchers believe that further efforts, including the EU-BIOMARKAPD project that is exploring alternative approaches to biomarker identification, may support the development of potential protein CSF biomarkers for clinical diagnosis or disease monitoring in early stage Parkinson’s disease.

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Simple Breath Test May Aid in Early Diagnosis of Parkinson’s, Study Reports

breath test

A new device that uses just a breath sample might, in the future, help diagnose early-stage Parkinson’s patients or identify those who may be at risk, according to researchers.  

The innovative technology, developed by researchers at the Israel Institute of Technology, was able to detect alterations in the breath of newly diagnosed Parkinson’s patients, even before they begin medication.

Although the device and collection method still needs to be perfected to reach the sensitivity of other diagnostic approaches such as brain ultrasound scans, researchers believe the tool shows promise.

Findings were reported in the study, “Sensor Array for Detection of Early Stage Parkinson’s Disease before Medication, published in the journal ACS Chemical Neuroscience.

The team had already tested its device in the past, and were able to detect differences in the exhaled breath of people already being treated for Parkinson’s disease and healthy controls.

Now they wanted to see if the device could detect differences in the breath of patients with early-stage Parkinson’s who were not yet on any medications.

The device consists of an array of 40 cross-reactive sensors based on gold nanoparticles or single-walled carbon nanotubes, attached to different chemical ligands. Each of these ligands can bind certain airy or volatile molecules in the breath that change the electrical signals of the sensor.

They tested the device on 29 patients who had recently been diagnosed with idiopathic Parkinson’s disease — with no known cause — and were not yet on medication, and 19 healthy individuals of similar ages, used as controls.

The device’s performance was also compared with other currently used diagnosed tests, namely brain ultrasonography and smell detection.

The sensor was able to distinguish Parkinson’s patients from controls with a sensitivity of 79%, a specificity of 84%, and accuracy of 81%, better than smell detection tests, which have 62% sensitivity, 89% specificity and 73% accuracy, and almost as good as brain ultrasound scans, at 93% sensitivity, 90% specificity, and 92% accuracy.

“[O]ur studies provide additional confirmation of the ability of our sensors array to detect altered breath VOC [volatile organic compounds] composition characteristic of PD [Parkinson’s disease],” the researchers wrote.

Early diagnosis of Parkinson’s can help patients begin neuroprotective therapies sooner, before extensive loss of dopamine-producing nerve cells — those affected in Parkinson’s disease — has occurred in the brain. However, to date, diagnosis is still subject to considerable errors.

So far, studies on early Parkinson’s diagnosis using volatile biomarkers have only been done in patients who are already being treated and medicated. “There is a great need to evaluate untreated patients for establishing a real world screening and diagnostic technology,” the authors said.

Further improvements, as well as more testing in patients, are still necessary for the device to reach the sensitivity of other diagnostic methods like brain ultrasound scans.

“Future development of the sensors array technique has the potential to produce a small, portable system with the advantage of unbiased determination which could be used in initial screening of at-risk subjects without the need for experienced clinical personnel,” the researchers concluded.

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Source: Parkinson's News Today

Pharma Two B Doses First Patients in Early-stage Parkinson’s Phase 3 Trial

P2B001 clinical trial

Israel’s Pharma Two B has dosed the first patients in a Phase 3 trial to evaluate the safety and efficacy of its drug candidate P2B001 to treat early-stage Parkinson’s disease.

P2B001 combines low-dose pramipexole and rasagiline, sold under the brand names Mirapex and Azilect. This new approach takes advantage of the well-known therapeutic effects and good safety profile of both Parkinson’s drugs, and combines it with Pharma Two B’s proprietary sustained-release formulation.

Given in low, controlled doses, P2B001 should manage symptoms better than existing drugs alone or in combination.

The trial (NCT03329508) will enroll 525 patients with untreated Parkinson’s disease, and will take place at about 70 sites in  the United States, Canada and Europe.

Researchers will divide patients into four treatment groups. The first will receive a once-daily P2B001 (pramipexole 0.6 mg/rasagiline 0.75 mg) combination product; the second, pramipexole 0.6 mg once a day; the third, rasagiline 0.75 mg once daily; and the fourth, pramipexole extended-release oral tablet titrated to optimal dose (1.5, 3.0 or 4.5 mg).

Each subject will participate in the study for 18 weeks including a 30-day screening period, a 12-week treatment period, and a two-week follow-up period.

The trial’s primary outcome is superiority of P2B001 (0.6/0.75 mg) compared to its individual components, pramipexole and rasagiline, on the total Unified Parkinson’s Disease Rating Scale (UPDRS) score.

Secondary outcomes include superiority of P2B001 (0.6/0.75 mg) as compared to pramipexole extended-release on the Epworth Sleepiness Scale (ESS) score, and efficacy of P2B (0.6/0.75 mg) as compared to its individual components in the change of Total Parkinson’s Disease Questionnaire 39 (PDQ39) score.

“We believe P2B001 has the potential to become a leading therapy for early stage PD,” Nurit Livnah, CEO of Pharma Two B, said in a press release. “Pharma Two B is focused on successfully completing our Phase 3 as planned and preparing for product launch in 2020. P2B001, once approved, is expected to provide early stage Parkinson’s patients with effective treatment with an improved safety profile.”

Advancing P2B001 into a Phase 3 trial was supported by positive results from the previous Phase 2b pivotal study (NCT01968460) in early-stage Parkinson’s patients.

The trial evaluated the efficacy of daily administration of two fixed doses of P2B001 — pramipexole 0.3 mg plus rasagiline 0.75 mg, or pramipexole 0.6 mg and rasagiline 0.75 mg — for up to 12 weeks compared to placebo. The study included 149 participants at 29 U.S. sites.

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Source: Parkinson's News Today