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‘Cocktail’ That Includes Alzheimer’s Therapy Boosts Cognitive Skills of Parkinson’s Dementia Patients, Study Finds

donepezil, dementia study

An oral combination that includes Aricept (donepezil) — an Alzheimer’s therapy — and Ginkgo biloba improved cognitive abilities and quality of life in people with Parkinson’s disease dementia (PDD) treated for six months, a study from China reports.

The study, “The efficacy of a ‘cocktail therapy’ on Parkinson’s disease with dementia,” appeared in the journal Neuropsychiatric Disease and Treatment.

Scientists at The Second Hospital of Baoding City investigated the efficacy and safety of combining Aricept tablets, butylphthalide and oxiracetam capsules, and Ginkgo biloba extract tablets to treat PDD.

Use of butylphthalide — a component of celery oil — has been associated with better thinking skills in people with vascular cognitive impairment but not dementia. Butylphthalide is thought to benefit the brain’s energy metabolism and blood circulation, and has been shown to ease learning and memory problems in a rat model of stroke.

Better cognitive function and brain metabolism are also associated with oxiracetam, while Ginkgo biloba extract has shown benefits in a rat model of dementia and improved thinking abilities in Parkinson’s patients with mild cognitive impairment.

Aricept (by Eisai and Pfizer) is an approved oral treatment for mild to moderate Alzheimer’s in the U.S., and recommended in China for PDD patients. It works by slowing the breakdown of acetylcholine at the synapse — the sites where nerve cells communicate — by blocking the acetylcholinesterase enzyme.

In this six-month study in 60 patients (32 men, mean age 68.6), 30 received a “cocktail” therapy consisting of 10 mg of Aricept (after a 5 mg dose over four weeks) once daily, and of 200 mg of dl-3n-butylphthalide, 800 mg of oxiracetam, and 80 mg of Ginkgo biloba extract given three times each day. The other 30 PDD patients served as controls, and received Aricept once daily.

All were treated between January 2011 and October 2016, and were using levodopa. To be diagnosed with Parkinson’s dementia, the patients’ cognitive problems had to impact their daily living abilities, and this diminishment had to be observed for at least one year after the onset of dyskinesia (the disease’s involuntary, jerky movements).

Patients’ cognitive function was assessed using the Montreal cognitive assessment scale (MoCA), the Blessed-Roth dementia scale, and the Clinical Dementia Rating Scale sum of boxes before treatment, and again at three and six months of treatment.

Results showed that people on the cocktail therapy had better scores across the three tests at six months in comparison to assessments made at the study’s start and at three months. No statistically significant differences were found among those in the control group.

Specifically, analysis of the different MoCA test components showed more significant benefits in visual-spatial ability and executive function, naming, attention, memory, and orientation with the combination treatment than with Aricept alone. Language skills and abstract thinking also improved in the combination treatment group relative to controls, but to a lesser degree, the study said.

The cocktail was also seen to have “good safety,” with rates of abnormal liver function similar between the two — 16.67% in the “cocktail” therapy and 13.33% in the controls. No adverse events related to the digestive system, nervous system, or allergies were noted over the course of treatment.

“Treatment with ‘cocktail therapy’ was safe and improved the conditions of patients with PDD, as well as the quality of life,” the scientists wrote. However, they cautioned that studies with larger groups of patients and longer treatment times are needed to verify the results.

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Participants Sought for Clinical Trial Testing ENT-01 for Parkinson’s Dementia

ENT-01

Enterin Inc has enrolled the first patient in its Phase 1b DEMET clinical trial investigating the effectiveness, safety and tolerability of small molecule ENT-01 to treat Parkinson’s disease dementia.

Contacts and locations of participating sites can be found here.

Many neurodegenerative disorders involve aggregation of misfolded (harmful) proteins in the brain. Parkinson’s is characterized by a buildup of the protein alpha-synuclein in the brain, which forms clumps known as Lewy bodies that damage and kill nerve cells.

In order to form aggregates, these clumps need to stick to the membranes that line the inside of neurons. It is the sticky form of alpha-synuclein protein that causes most of the damage seen in Parkinson’s, more so than if this protein was freely floating within a neuron.

ENT-01 (kenterin) enters neurons from the enteric nervous system (ENS), attaches itself to the nerve cells’ membrane and dislodges Parkinson’s-related alpha-synuclein clumps. By unsticking harmful alpha-synuclein, the investigational treatment reduces the amount of alpha-synuclein aggregates within neurons and, in theory, cellular death.

The enteric nervous system is a network of neurons that independently governs the function of the gastrointestinal tract. Previous studies claim that alpha-synuclein begins accumulating in the ENS and then travels from the gut to the brain, where it is linked to the development and progression of Parkinson’s.

The multicenter, randomized, double-blind DEMET study (NCT03938922) will assess ENT-01’s effectiveness, safety and tolerability in patients diagnosed with Parkinson’s disease dementia. It expects to enroll 40 participants (aged 30 to 90 years), who will be assigned randomly to receive ENT-01 or a placebo tablet. Both will be taken once a day.

By being taken orally, and because ENT-01 is not absorbed into the bloodstream, the molecule will solely act on the gut’s neurons, changing the communication between the gut and brain.

The trial will be conducted on an outpatient basis and each patient will have to visit the clinic five times. The study’s primary goal is to evaluate if the experimental therapy improves cognition in people with Parkinson’s  dementia. Investigators also will assess ENT-01’s effects on attention, social function and frequency and/or severity of hallucinations/delusions.

In two separate Phase 2 clinical trials, NCT03047629 and NCT03781791, ENT-01 has been shown to ease both motor and non-motor symptoms of Parkinson’s, indicating its potential to change disease progression.

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Higher Mortality Rates Found in Patients with Parkinson’s Dementia, Lewy Body Dementia, Study Shows

higher mortality rates

Patients diagnosed with Parkinson’s disease dementia (PDD) and dementia with Lewy bodies (DLB) were found to have a mortality rate more than three times higher than the general population, according to researchers in Sweden.

The 10-year follow-up study, titled “Relative survival in patients with dementia with Lewy bodies and Parkinson’s disease dementia,” was published in the journal PLOS One.

DLB is a neurodegenerative disorder caused by the accumulation of alpha-synuclein protein clumps, leading to physical and cognitive damage.

The alpha-synuclein protein clumps and associated symptoms are also found in a large group of patients with Parkinson’s disease who develop dementia.

Years of research identified a link between the diagnosis of dementia and increased mortality. But the mortality levels greatly depend on dementia type, gender, and study design.

In the general population with dementia, late diagnosis, male gender, the existence of multiple coexisting conditions (comorbidities), and functional disability have been linked to shorter survival.

A research team from Skåne University Hospital in Malmö, Sweden, studied the survival of patients with PDD and DLB compared with the general population. To better understand survival in these groups, the team identified predictors of excessive mortality.

Researchers retrospectively studied 177 patients diagnosed with PDD or DLB from 1997 to 2014 at the Memory Clinic in Malmö. Data collected included demographics, time of first visit, time of diagnosis, comorbidities, apolipoprotein E (APOE) genotyping — a test used to assess a person’s susceptibility for Alzheimer’s disease — and the mini-mental state examination score at the time of diagnosis.

Of the 177 patients included in the study, 131 had DLB, while 46 were diagnosed with PDD. All these patients had at least one comorbidity due to the diagnosis of dementia.

A total of 143 patients (81%) had died by the time of follow-up, with a median survival of 4.1 years.

At a five-year follow-up, the mortality ratio — the ratio between the number of PDD/DLB patients’ deaths over the number of deaths in the general population — was 3.02, and at 10 years, it was 3.44, indicating that PDD and DLB patients have mortality rates more than three times higher than the general population.

Researchers also found that survival was worse if the patients were diagnosed at a younger age, were female, and showed lower scores on the cognitive test.

A more detailed analysis revealed higher mortality in DLB patients who were positive for the APOE test, but not in PDD patients who tested positive in APOE.

This retrospective study demonstrated a higher mortality rate in patients with PDD and DLB compared with the general population 10 years after the diagnosis of the disease.

Also, younger patients, females, and those who tested positive for APOE are linked to excess mortality.

“In conclusion, mortality in patients diagnosed with Lewy bodies and Parkinson’s disease dementia is over three times higher in patients during a ten-year follow-up, compared to persons in the general population unaffected by the disease,” the researchers wrote.

“Excess mortality is found primarily in younger patients, females and carriers of APOE. Further research is required regarding survival and possible interventions, including disease-modifying treatments, to improve care and prognosis for these patients,” they added.

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Source: Parkinson's News Today

Neuropsychiatric Symptoms, Alpha-Synuclein Levels May Help Distinguish Dementia-Related Diseases

neuropsychiatric symptoms

Neuropsychiatric symptoms, combined with levels of alpha-synuclein, can be used to distinguish dementia with Lewy bodies from Parkinson’s disease dementia and Alzheimer’s disease, a study shows.

The study, “Neuropsychiatric symptoms and α-Synuclein profile of patients with Parkinson’s disease dementia, dementia with Lewy bodies and Alzheimer’s disease,” was published in the Journal of Neurology.

Lewy body dementia is the second most common type of degenerative dementia after Alzheimer’s disease. It includes two clinical diagnoses, dementia with Lewy bodies and Parkinson’s disease dementia, which share essentially the same array of symptoms, and are associated with the formation of Lewy bodies and subsequent nerve cell death. Lewy bodies are abnormal aggregates of alpha-synuclein protein that develop inside nerve cells.

Based on international consensus, when cognitive impairment begins within one year of the onset of parkinsonian motor signs, the patient is diagnosed with dementia with Lewy bodies, whereas the diagnosis is Parkinson’s disease if cognitive impairment develops more than a year after the appearance of motor symptoms.

Dementia with Lewy bodies, Parkinson’s disease dementia, and Alzheimer’s disease have similar behavioral and psychological symptoms, which can be challenging for an accurate diagnosis.

Researchers in this study evaluated whether neuropsychiatric symptoms and/or alpha-synuclein levels could be used to distinguish between these dementia-related disorders.

Between 2013 and 2015, the team recruited 63 participants, with a mean age of 71.5, from the register-based database of the Memory and Movement Disorder Inpatient Unit at Eginition University Hospital in Athens, Greece.

Of these patients, 28 had dementia with Lewy bodies, 19 had Alzheimer’s disease, and 16 had Parkinson’s disease dementia. Patients’ demographic and clinical characteristics were collected.

Neuropsychiatric symptoms were assessed through the 12-item Neuropsychiatric Inventory (NPI), a reliable instrument for screening the frequency of dementia-related behavioral symptoms, including delusions, hallucinations, agitation, depression, anxiety, euphoria, apathy, sleeping problems, and eating/appetite behavior.

Participants’ caregivers were interviewed by a trained neuropsychologist to assess NPI scores on the basis of observations within the past month.

Levels of alpha-synuclein were assessed in samples of cerebrospinal fluid — the fluid that fills the brain and spinal cord — of each patient.

Patients with Parkinson’s disease dementia and dementia with Lewy bodies had significantly more hallucinations than Alzheimer’s patients. Those who had dementia with Lewy bodies had significantly more agitation and sleeping problems than patients with Parkinson’s disease dementia and Alzheimer’s patients, respectively.

In fact, patients with dementia with Lewy bodies showed significantly higher total NPI scores and levels of alpha-synuclein than other patients.

Additional analysis showed that the combination of high burden of neuropsychiatric symptoms — reflected in elevated NPI scores — and increased levels of alpha-synuclein could strongly predict a diagnosis of dementia with Lewy bodies among all patients.

This suggests that these two parameters could be used to distinguish dementia with Lewy bodies from Parkinson’s disease dementia and Alzheimer’s disease.

“If verified in future studies, these novel findings could serve to pave the way for a more accurate diagnosis of DLB [dementia with Lewy bodies] based on the combination of biomarkers and neuropsychiatric profile,” the researchers wrote.

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Source: Parkinson's News Today

Eli Lily Recruiting for Phase 2 Trial to Test LY3154207 for Parkinson’s Dementia

LY3154207 study

Eli Lilly is recruiting patients for its Phase 2 clinical trial evaluating LY3154207 as a potential treatment for Parkinson’s disease dementia (PDD).

Parkinson’s disease destroys the nerve cells that make dopamine, a key player in nerve cell communication and involved in movement control, cognition, memory, learning, attention, and sleep.

Parkinson’s main affected brain area is the substantia nigra, which controls movement, but as the disease progresses and spreads in the brain, it can affect the areas responsible for mental functions, memory, and judgment.

About 50 percent of Parkinson’s patients will experience some form of cognitive impairment, which is diagnosed as Parkinson’s disease dementia when it affects more than one area of cognition and is severe enough to impair social or work functioning.

Symptoms of PDD can include attention difficulties, forgetfulness, and slow thought processes. This can make communication difficult, as remembering words and names and following conversations can be challenging.

Eli Lilly is developing LY3154207, an orally administered enhancer of dopamine receptor D1 — a type of dopamine receptor involved in cognition — for the treatment of PDD.

Previous preclinical studies have shown that enhancing dopamine receptor D1 can improve cognitive function, including attention.

In March 2017, a Phase 1 study (NCT02562768) evaluating LY3154207’s safety, tolerability, and how the body processes the therapy, was completed in healthy volunteers and Parkinson’s patients.

Now, a randomized placebo-controlled Phase 2 study called PRESENCE (NCT03305809) will evaluate the safety and effectiveness of three doses of LY3154207 in patients with mild-to-moderate Parkinson’s disease dementia.

Ely Lilly seeks to enroll 340 individuals, 46-85 years old, in centers from four countries: U.S., Canada, China, and Puerto Rico. Participants must have Parkinson’s disease with at least two years of symptoms, have PDD with a decline in cognitive function leading to functional impairment, have no history of a stroke in the past six months, and no signs/diagnosis of psychotic diseases.

Participants will be chosen randomly to receive daily either one of the three doses of LY3154207, or a placebo, for 12 weeks.

The study’s main goal is improvement in the ability to sustain concentration for a period of time without error —assessed through the Continuity of Attention (CoA) Composite Score of the Cognitive Drug Research Computerized Cognition Battery (CDR-CCB).

Secondary goals include improvements in cognitive function and attention, daytime sleepiness, dementia-related behavioral symptoms, activities of daily life, and motor function.

The PRESENCE study is estimated to conclude by July 2019.

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Source: Parkinson's News Today

Phase 2 Study of Potential Oral Therapy for Parkinson’s Dementia, Anavex 2-73, Planned

Anavex 2-73

Anavex Life Sciences is planning to open a Phase 2 clinical trial testing Anavex 2-73, a potential oral treatment for patients with Parkinson’s disease dementia (PDD), this year.

Anavex 2-73 aims to treat PDD by binding to the sigma-1 receptor, located in a cellular structure called the endoplasmic reticulum and important to protein production and transport.

The proposed double-blind, placebo-controlled trial will evaluate Anavex 2-73’s ability to ease both cognitive and motor difficulties in Parkinson’s patients. A trial application is before European regulators, with plans to start this study in the second half of 2018.

According to the Parkinson’s Foundation, around 50 to 80 percent of Parkinson’s patients will develop disease-related dementia. Parkinson’s is characterized by the loss of neurons in a crucial brain area that controls movement, the substantia nigra. This loss, in turn, lowers brain levels of dopamine, a key player in nerve cell or neuronal communication.

With disease progression, these changes spread to other areas of a patient’s brain, affecting memory, attention, and thinking and reasoning.

“As many as 80 percent of people with Parkinson’s will experience Parkinson’s disease dementia and treatment options are limited,” Christopher Missling, president and CEO at Anavex, said in a press release.

Results of preclinical work, fully funded by the The Michael J. Fox Foundation for Parkinson’s Research, show that treatment with Anavex 2-73 was able to restore function to damaged nerve cells in mouse models of Parkinson’s disease. Data also demonstrated that it targets misfolded proteins and poorly working mitochondria — a cell’s energy source — to prevent oxidative stress, inflammation, and cellular stress.

“We are excited to progress our program to Phase 2, with a focus on the many patients with Parkinson’s disease dementia, and we remain focused on the discovery and development of potential treatments for neurological diseases with unmet needs, including Alzheimer’s disease and Rett syndrome,” Missling added.

Anavex filed an updated investigational new drug application to the U.S. Food and Drug Administration (FDA) earlier this year for a double-blind, Phase 2 study evaluating Anavex 2-73 in Rett syndrome. If approved, this trial is also expected to open in late 2018.

The company plans to open a Phase 2/3 trial of Anavex 2-73 in up to 300 people with mild-to-moderate forms of Alzheimer’s disease.  A Phase 2a dose-escalating study (NCT02244541) involving 32 people with probable Alzheimer’s was conducted at sites across Australia.

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Source: Parkinson's News Today

Explaining Cognitive Dysfunction in Parkinson’s Disease

In this video from the Michael J. Fox Foundation for Parkinson’s Research, Dr. Rachel Dolhun, neurologist and movement disorder specialist, talks about cognitive dysfunction in Parkinson’s disease patients.

MORE: Four possible causes of Parkinson’s disease

Dr. Dolhun explains that cognitive dysfunction is a non-motor symptom whereby a person’s memory or thinking ability is compromised. It can happen at any point in Parkinson’s disease and the severity can vary from patient to patient. She then talks about the brain cell changes that occur in Parkinson’s disease patients and how cognitive dysfunction can lead to dementia.

MORE: Boxing therapy can help young-onset Parkinson’s disease

Parkinson’s News Today is strictly a news and information website about the disease. It does not provide medical advice, diagnosis or treatment. This content is not intended to be a substitute for professional medical advice, diagnosis, or treatment. Always seek the advice of your physician or another qualified health provider with any questions you may have regarding a medical condition. Never disregard professional medical advice or delay in seeking it because of something you have read on this website.

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