Memory-related Mild Cognitive Impairment May Be Linked to More Severe Alpha-Synuclein Buildup, Researchers Say

Alpha-Synuclein Buildup

Memory-related mild cognitive impairment in Parkinson’s disease may be associated with a more severe buildup of alpha-synuclein protein in the brain — such as that observed in more advanced stages of the disease, a study finds.

The results of the study, “Neuropathological Findings in Parkinson’s Disease With Mild Cognitive Impairment,” were published in Movement Disorders.

Studying neuropathological markers — meaning the molecular, cellular, or tissue abnormalities characteristic in a given disease — in people with neurological disorders like Parkinson’s allows doctors and scientists to better understand the different tissue changes that contribute to the disease mechanism of a given disorder.

Parkinson’s is a multisystem neurodegenerative disorder with motor and non-motor features caused by the selective death of midbrain dopamine-producing neurons. These nerve cells die because of the aggregation, or clumping together, of a protein called alpha-synuclein in structures commonly known as Lewy bodies. Alpha-synuclein is associated with the regulation of the release of dopamine, the neurotransmitter involved in controlling the start and stop of voluntary and involuntary movements.

Although cognitive impairment is one of the most common non-motor complications of Parkinson’s, not much is known about the molecular and brain abnormalities that characterize it. The studies that do exist indicate that Lewy body protein aggregates coexist with amyloid plaques, neurofibrillary tangles, and inflammation — all of which are also observed in Alzheimer’s disease.

To bridge this knowledge gap, a group of researchers now sought to determine the molecular, cellular, and tissue features that underlie Parkinson’s disease with mild cognitive impairment. The work was a collaboration between the Mayo Clinic in Arizona, the Barrow Neurological Institute, also in Arizona, the Banner Sun Health Research Institute in Arizona, the Cleveland Clinic in Ohio, and the University of California-Davis. The team used autopsy data from the Arizona Study of Aging and Neurodegenerative Disorders.

The scientists compared brain tissue abnormalities of people with amnestic mild cognitive impairment (MCI) with those of patients with non-amnestic MCI. Amnestic MCI is a type of mild cognitive impairment that primarily affects memory, while non-amnestic MCI affects thinking skills other than memory, including the ability to make decisions or visual perception.

Out of 736 screened individuals, 159 had pathologically defined Parkinson’s disease. Of these, only 25 — eight women and 17 men, ages 69-92 — had concurrent mild cognitive impairment. A total of 14 (56%) autopsied subjects had amnestic MCI while 11 (44%) had non-amnestic MCI.

The results revealed that each individual with Parkinson’s disease with mild cognitive impairment had significantly distinct molecular and tissue abnormalities from every other study subject with an identical diagnosis. Consequently, the scientists found no specific set of molecular, cellular, or tissue changes that they could reliably allocate to cognitive impairment in Parkinson’s.

Alpha-synuclein accumulation was more severe in some cases than others, and there were Alzheimer’s disease-related features — including neuritic plaques, neurodegeneration of cerebral white matter, and cerebral amyloid angiopathy, or amyloid buildup on the walls of brain arteries — in these patients’ brain samples. The scientists also observed that patients had a specific genetic variant of the apolipoprotein (APOE) gene, called APOE4, the most prevalent genetic risk factor for Alzheimer’s disease.

Importantly, non-amnestic patients had a significant increase in the severity of Lewy body pathology, or alpha-synuclein buildup, compared with amnestic subjects — 63% versus 21%.

The scientist note that there are apparently distinct biological mechanisms between Alzheimer’s and Parkinson’s disease. However, these neurodegenerative disorders seem to overlap to some extent.

While this is a relatively small study, the findings suggest that despite significant heterogeneity in cellular and tissue abnormalities, Parkinson’s patients with amnestic mild cognitive impairment might be more prone to greater alpha-synuclein accumulation.

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Dosing Underway in Phase 1 Trial of AL101 for Potential Treatment of Parkinson’s, Other Disorders

AL101 Phase 1 trial

Dosing has begun for healthy volunteers in a Phase 1 clinical trial of AL101, which has the potential to treat neurodegenerative disorders such as Parkinson’sAlector recently announced.

The randomized, placebo-controlled trial (NCT04111666) is testing the safety, tolerability, pharmacokinetics (how the compound moves throughout the body), and pharmacodynamics (how the body interacts with the compound) of intravenously (into the vein) and subcutaneously (under the skin) administered doses of AL101.

The trial, which is not yet recruiting, is expected to enroll up to 42 healthy volunteers and will take place at a single study site in Orlando, Florida. More information can be found here.

Participants will be randomized to receive either a single subcutaneous dose, or up to three ascending intravenous doses of AL101. Safety and tolerability will be measured by the occurrence of adverse events over the course of 85 days.

AL101 is a compound designed to increase progranulin levels in the brains of people with neurodegenerative diseases. It is Alector’s second progranulin-stimulating therapeutic candidate to enter clinical trials in the past two years.

Low levels of progranulin have been linked to neurodegeneration and lysosomal storage disorders. Studies conducted in animals have shown that increasing progranulin protects against the progression of several of these disorders, including Parkinson’s.

A human monoclonal antibody, AL101 is designed to attach itself to receptors on specific cells and trigger the production of progranulin.

“This study will pave the way for exploring multiple indications for progranulin therapy as well as delivery formulations of this novel investigational medicine. The results will inform our decisions on future development of AL101 for neurodegeneration,” Robert King, PhD, chief development officer of Alector, said in a press release.

The U.S. Food and Drug Administration awarded AL101 orphan drug designation for frontotemporal dementia (FTD) in July 2019. Orphan drug status is given to investigational therapies that have the potential to treat a rare disease for which there is an unmet need. The designation grants Alector certain incentives such as additional support from the FDA and a period of marketing exclusivity in the event the therapy is approved.

Because proglanulin is implicated in Parkinson’s and Alzheimer’s disease, as well as FTD, AL101 has the potential to benefit all three disorders.

Alector is a clinical stage biopharmaceutical company based in South San Francisco. The company focuses on neurodegeneration and seeks to leverage the body’s own immune programs to treat neurodegenerative disorders. By engaging innate immune responses, Alector’s therapies could simultaneously counteract multiple disorders.

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Phase 1 Trial Opens into Potential Parkinson’s Therapy, Anle138b

Phase 1 trial opens

A Phase 1 clinical trial of MODAG Neuroscience Solutions’ lead candidate anle138b is now underway and recruiting healthy participants at its one site in Nottingham, England, to study the compound’s safety.

The small molecule is being developed to treat multiple system atrophy (MSA), but holds the potential to be used in other diseases caused by clumping of the protein alpha-synuclein, such as Parkinson’s disease.

“With the start of this trial, we are on track to run the tests necessary to bring anle138b one step closer to patients,” Torsten Matthias, PhD, chief executive officer of MODAG, said in a press release.

Many neurodegenerative disorders involve the aggregation of misfolded (harmful) proteins in the brain. Anle138b works by binding to harmful forms of alpha-synuclein — a key protein involved in Parkinson’s disease — to clear the brain of existing clumps and to prevent new clumps, also known as Lewy bodies, from forming.

The compound has been shown to reduce the buildup of these toxic clumps and delay disease progression in models of MSA, Parkinson’s, and Alzheimer’s disease. Moreover, anle138b was found to reverse Parkinson’s-related motor symptoms in mice models of the neurodegenerative disorder.

This Phase 1 study’s primary goal is to evaluate the safety and tolerability of oral anle138b in healthy volunteers. Secondary objectives include dose-finding evaluations and assessments of its pharmacokinetics  — essentially how a compound is absorbed, distributed, metabolized, and excreted by the body.

Recruitment is ongoing and being overseen by Quotient Sciences in Nottingham.

“Anle138b has the potential to become a tangible treatment option to stop MSA, a highly underserved indication, in its tracks. MSA patients are severely impacted by progressing movement, balance and autonomic function impairments and as with many neurodegenerative diseases, there are no disease-halting treatment options available,” said Johannes Levin, MD, chief medical officer of MODAG.

“If successful, the Phase 1 trial also opens the opportunity for MODAG to investigate anle138b in other Parkinsonian disorders and Parkinson’s itself,” Levin added.

The biotech company has already secured a worldwide patent for anle138b.

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Report Highlights Potential Benefits of Drinking Coffee in Neurodegenerative Diseases, Including Parkinson’s


Drinking coffee regularly may help reduce the risk of neurodegenerative diseases — including Parkinson’s disease — particularly in men, according to a new report from the Institute for Scientific Information on Coffee (ISIC).

With the substantial improvements in medical care, health, and quality of life over the past decades, global life expectancy has risen to 72 years (latest data, 2016), according to the World Health Organization.

Nevertheless, longer life expectancies come with increased risk of disease and disabilities. It is estimated that up to 10 million people worldwide are living with Parkinson’s disease, the second most common age-related neurodegenerative disease after Alzheimer’s.

Increasing evidence suggests that lifestyles — such as diet, caffeine/coffee consumption, and smoking — may contribute to people’s risk of developing Parkinson’s and other neurodegenerative conditions.

In particular, previous preclinical studies have shown that some coffee components (caffeine combined with EHT, and phenylindane) can prevent the formation of the toxic protein aggregates associated with Parkinson’s development.

The ISIC’s new report discusses the association between dietary components, particularly coffee and its components, and a reduced risk of neurodegenerative disorders, including Parkinson’s and Alzheimer’s.

The report was written by Elisabet Rothenberg, PhD, a dietitian and an associate professor at the Food and Meal Science department of Kristianstad University, Sweden.

While the link between diet and Parkinson’s disease is still largely ambiguous, likely due to underlying genetic and gender-specific factors, increasing evidence suggests that diet and dietary compounds may influence the risk of developing the disease.

A recent review study highlighted the potential protective effect of a Mediterranean diet, uric acid, good polyunsaturated fats, coffee, caffeinated tea, as well as beer in Parkinson’s development, particularly in men. Uric acid is an antioxidant molecule formed with the break-down of purines, which are compounds found in several foods, including liver, shellfish, sardines, and alcohol.

Meanwhile, other data suggest that consumption of dairy products and saturated fats may increase Parkinson’s risk.

The first reports about coffee consumption and the lower risk of Parkinson’s were published in the 1970s. Since then, several studies have analyzed its potential protective properties.

Available data suggest that drinking coffee reduces the risk of developing Parkinson’s disease by up to 30%, in a dose-dependent manner, with most studies indicating three cups of coffee as the beneficial dose. However, the best dose of coffee and caffeine consumption is still unclear.

Besides its potential effect on the risk of Parkinson’s disease, coffee consumption also has been suggested to help ease Parkinson’s symptoms both in animal models and in patients.

Several studies also have highlighted that men may benefit more than women from being coffee drinkers, with some studies showing an up to 60% reduced risk of Parkinson’s disease among male coffee drinkers.

This potential gender-specific benefit may be explained by underlying hormonal and genetic factors and/or the lower frequency of Parkinson’s disease among women. Preclinical studies in mouse models of the disease suggest that a competition between estrogen and caffeine may be behind this gender difference.

Notably, while some studies have found an association between the non-use of postmenopausal hormones and coffee drinking in the reduction of Parkinson’s risk in women, more recent studies have shown the opposite trend.

Overall, additional studies are required to better understand these potential associations and their underlying mechanisms, as well as to clarify gender differences and interactions between hormones and coffee compounds.

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Study Will Test Brain’s Natural ‘Plumbing System’ in Parkinson’s, Alzheimer’s Mice


Parkinson’s UK and Alzheimer’s Research UK have teamed up to help fund a project that will test whether a “waste disposal system” in the brain could be exploited to help in the understanding and treatment of these diseases, Parkinson’s UK announced.

The new project, which is expected to take about three years to complete, will focus specifically on the glymphatic system. This system, which was  discovered only recently, helps to remove waste products from the brain.

The general idea behind the project is that, since both neurological diseases are associated with the abnormal and toxic buildup of “clumps” of protein in the brain (tau for Alzheimer’s and alpha-synuclein for Parkinson’s), activating the glymphatic system could help remove these clumps and, by extension, fight the disease.

“Studying how the glymphatic system affects the clearance of two distinct protein species that both accumulate in the brain and cause neurodegeneration means we’ll be able to understand how best to harness the power of the system. This will hopefully allow us to provide a new therapeutic target for treatment of the conditions,” Ian Harrison, PhD, said in a press release. Harrison, a professor at University College London, will lead the project.

The glymphatic system is a functional waste clearance pathway for the central nervous system (brain and spinal cord); it works as the brain’s unique method to remove waste. It consists of a “plumbing system” that takes advantage of the brain’s blood vessels and pumps cerebral spinal fluid through the brain’s tissue, flushing away waste.

This system is highly active during sleep, clearing away toxins responsible for Parkinson’s and other neurological disorders.

Using mouse models, Harrison and other researchers will track how tau and alpha-synuclein spread in the brain after the glymphatic system’s activity has been altered (either diminished or increased). It also will determine the effect this change has on mouse behaviors that are related to neurological diseases, such as memory and movement capabilities.

Previous research has suggested that sleep, exercise and low levels of alcohol could help activate the glymphatic system. The new project will build on these findings; researchers also will investigate potential new therapies to target this system.

“This is the first time we’ll be studying the glymphatic system’s role in clearing toxic proteins, and the potential it provides for developing new treatments which are urgently needed by people living with Parkinson’s,” said David Dexter, PhD, deputy director of research at Parkinson’s UK.

Sara Imarisio, PhD, the head of research at at Alzheimer’s Research UK, added: “The causes of Alzheimer’s disease are complex. While there are many differences between Parkinson’s and Alzheimer’s, common biology between both diseases means that research into one condition can provide important insights into the other. This new research could shed light on a disease process that holds potential as a target for future drugs, and that could change the course of Alzheimer’s and other neurodegenerative diseases.”

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Treatment with Intranasal Insulin May Improve Verbal Fluency and Motor Function, Early Study Shows

Intranasal insulin

Treatment with intranasal insulin — which is atomized into a spray and inhaled through the nose — may ease Parkinson’s disease-related cognitive impairment and motor symptoms without dangerously lowering blood sugar levels, according to a proof-of-concept trial.

The study, “Safety and preliminary efficacy of intranasal insulin for cognitive impairment in Parkinson disease and multiple system atrophy: A double-blinded placebo-controlled pilot study,” was published in PLoS ONE.

Insulin, which regulates sugar (glucose) levels in the blood, is known to have potent effects in the brain, including on cognition. Intranasal insulin treatment has been shown to increase functional connectivity in the brain in type 2 diabetes without changing serum glucose levels.

Evidence also indicates that intranasal insulin improves visuospatial (visual perception of the spatial relationships between objects) and verbal short-term memory in people with mild cognitive impairment due to Alzheimer’s disease.

Cognitive impairment is a common non-motor complication of Parkinson’s disease. However, the effects of intranasal insulin on this particular complication remain to be understood.

In this study, researchers from Harvard Medical School and University of Massachusetts designed a randomized, placebo-controlled, single-center Phase 2 trial (NCT02064166) to evaluate the effectiveness of intranasal insulin as a treatment for individuals with Parkinson’s and multiple system atrophy (MSA). The symptoms of MSA are similar to those seen in Parkinson’s, but the disorder has a quicker progression and a much shorter survival rate.

A total 14 patients, comprised of nine men and five women, were randomly assigned to receive 40 international units (IU) of intranasal insulin or saline once daily for four weeks. Nine individuals were included in the insulin group and the remaining six were allocated to the placebo group.

Participants were diagnosed and treated for Parkinson’s disease, with one subject in the insulin group also treated for possible multiple system atrophy.

During the trial, participants completed a screening visit, a baseline assessment, two follow-up visits, and an end-of-treatment assessment. Researchers performed neuropsychological testing, and evaluated patients’ motor function — using several disease severity scales and a walking test — and disease progression.

Participants kept taking their usual medications. The last intranasal insulin or placebo dose was given on the day of post-treatment assessment.

The intranasal therapy was safe and well-tolerated and there were no treatment-related side effects. Importantly, blood glucose levels remained normal in treated individuals.

Results revealed patients who received the insulin had better verbal fluency than those given the placebo. Compared with their pre-treatment assessments, individuals given insulin also had decreased disease severity and motor scores — indicating their motor symptoms were eased by treatment and that the Parkinson’s did not progress as fast.

Interestingly, the patient with probable multiple system atrophy, who was included in the insulin group, remained stable during the study and showed a tendency toward improvement of motor skills.

“Although this is a single case of INI [intranasal insulin] treatment in MSA [multiple system atrophy], it warrants further investigation as there are no therapies available to modify disease progression,” the researchers said.

No changes were observed in cognitive, depression, or gait assessments within and between groups.

“Our study provided preliminary data that suggested an improvement of functional skills after four weeks of daily INI [intranasal insulin] treatment that paves the way toward a larger cohort study to evaluate long-term safety and potential efficacy of intranasal insulin administration for potential treatment and prevention of functional decline in patients with Parkinson disease,” the study concluded.

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Phase 2 Trial Testing Anavex 2-73 Recruiting Parkinson’s Patients With Dementia in Spain

Anavex 2-73 enrolling trial

The first patient has been enrolled in Anavex Life Sciences‘ Phase 2 clinical trial to evaluate the potential and safety of Anavex 2-73 as a treatment for Parkinson’s disease dementia.

Now actively recruiting, the study (2017-004335-36) is expected to enroll approximately 120 Parkinson’s patients ages 50 or older with a dementia diagnosis. It is being conducted across several clinical sites in Spain, and has received the support of the Michael J. Fox Foundation for Parkinson’s Research and León Research.

Anavex has been developing Anavex 2-73 as a potential disease-modifying therapy for Alzheimer’s disease. It is a small molecule that activates the sigma-1 receptor located in a cellular structure called the endoplasmic reticulum, which is critical for several cellular regulatory mechanisms.

“We are very pleased to initiate our first patient enrollment into the Parkinson’s disease dementia Phase 2 study of Anavex 2-73,” Christopher U. Missling, PhD, president and CEO of Anavex, said in a press release. “This is an important step toward achieving clinical data for the second indication initiating this year for Anavex 2-73 also incorporating genomic precision medicine biomarkers.”

Trial participants will be randomly assigned to receive orally 10 or 20 mg of Anavex 2-73 or a placebo for 14 weeks.

Researchers will evaluate the impact of the treatment on cognition, as determined by the cognitive drug research computerized assessment system, as well as on patients’ motor function and sleep quality.

During the study, researchers will also assess genomic precision medicine biomarkers associated with Anavex 2-73 that were identified in another Phase 2 trial (NCT02244541) in Alzheimer’s disease.

Additional information (in Spanish) on the trial can be found here. Patients and caregivers interested in taking part in the study can download and fill out a simple screening questionnaire that is available on the website to assist in discussions with their physician.

“Parkinson’s disease is an already prevalent disease among older individuals that is poised to become a much greater public health problem around the globe in the coming decades and is now appreciated commonly to cause cognitive impairment, including dementia, and behavioral changes,” Jaime Kulisevsky, MD, PhD, principle investigator of the Phase 2 trial, as well as a professor at the Autonomous University of Barcelona and director of the Movement Disorders Unit of the Sant Pau Hospital in Barcelona.

Results from preclinical studies have shown that Anavex 2-73 has the potential to restore function to damaged nerve cells in mouse models of Parkinson’s disease. The compound was also found to target faulty proteins and poorly working mitochondria — the cells’ powerhouses — preventing oxidative stress and inflammation.

As of now, only one medication, Nuplazid (pimavanserin) is approved by the U.S. Food and Drug Administration for the treatment of hallucinations and delusions associated with Parkinson’s disease.

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Trial to Test New Imaging Agent for Visualizing Synapses in Living Brain

Imaging agent for synapses

Rodin Therapeutics will evaluate a new imaging agent that allows the visualization of human synapses — the junctions between two nerve cells that allow them to communicate — in the living brain.

Results from the study will guide the company’s upcoming Phase 1b trial of a new therapeutic compound designed to strengthen and increase the number of synapses in patients with neurologic diseases, including Parkinson’s.

Several neurological and psychiatric diseases are characterized by defective synapses. However, there is currently no way to visualize synapses in the living brain. Tissues would need to be sampled, an invasive and unwanted procedure.

The new imaging agent, a radiotracer called [11C]UCB-J, targets the synaptic vesicle glycoprotein 2A (SV2A) and is used in positron emission tomography (PET). This protein regulates the release of neurotransmitters — chemical messengers used by the nervous system to transmit messages between neurons, or from neurons to muscles — at the synapse.

PET imaging uses small amounts of radioactive materials, called radiotracers, along with a special camera and computer to help evaluate organ and tissue function.

The trial, which will include both healthy volunteers and patients with Alzheimer’s disease, will produce brain scans following administration of the radiotracer. Participants will undergo scans at the beginning of the trial (baseline) and 28 days later.

The trial will determine the radiotracer’s robustness and potential usefulness in future trials.

“Most neurodegenerative disorders, including Alzheimer’s disease and Parkinson’s, are associated with deteriorating synapses — but until now, physicians and researchers have not been able to measure synaptic density in a living patient. This PET scan should allow us to visualize brain synaptic density in patients and possibly track their response to therapies over time,” J. Michael Ryan, MD, Rodin’s chief medical officer, said in a press release.

“Measuring synaptic density in a living human being holds tremendous potential for the diagnosis and treatment of a variety of neurologic diseases. We’re excited to be one of the first research centers to utilize this new imaging technology,” said Peter Paul De Deyn, MD, Ph.D., director of the Alzheimer’s Research Center Groningen, the Netherlands, one of the centers where the trial will take place.

“This tool has the potential to shape future clinical trials by offering an early signal about whether an investigational drug is driving molecular and structural changes in the brain,” said Philip Scheltens, MD, Ph.D., who directs the Alzheimer’s Center at VUmc, Amsterdam, another trial center. “We can then take the next step and assess whether those changes lead to functional and cognitive improvements in patients with neurodegenerative diseases.”

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DNA Mutations Acquired Before Birth May Lead to Parkison’s in Adulthood, Study Suggests

DNA mutations and brain development

Spontaneous mutations that occur in DNA before birth — part of cell division and reproduction in the growing brain — can predispose a person to neurodegenerative diseases in adulthood and may be more common than thought, a research team led by the University of Cambridge suggests.

Its findings may explain the onset of such disorders in people without a family history of diseases like Alzheimer’s and Parkinson’s.

The study, “High prevalence of focal and multi-focal somatic genetic variants in the human brain,” was published in Nature Communications.

The causes of neurodegenerative diseases are essentially unknown. Most are sporadic — meaning they simply appear in a person —  although hereditary cases are known and well-documented.

Clinical presentation of hereditary forms is frequently like the sporadic types, suggesting that common biological processes underlie both forms of neurodegenerative diseases.

“As the global population ages, we’re seeing increasing numbers of people affected by diseases such as Alzheimer’s, yet we still don’t understand enough about the majority of these cases,” Patrick Chinnery, the study’s lead author, said in a press release.

“Why do some people get these diseases while others don’t? We know genetics plays a part, but why do people with no family history develop the disease?” added Chinnery, who is also with the Medical Research Council (MRC) Mitochondrial Biology Unit and a professor in the Department of Clinical Neurosciences at Cambridge.

Chinnery’s team hypothesized that spontaneous mutations within specific clusters of brain cells could contribute to the misfolded protein synthesis found in neurodegenerative diseases, and that such molecular phenomenon could have the potential to spread throughout the brain as a person aged.

Investigators used frozen brains acquired from the Newcastle Brain Tissue Resource, part of MRC’s U.K. Brain Banks Network. Among the 54 brains examined, 20 were from people with Alzheimer’s, 20 with those Lewy body dementia, and 14 who had no family history of any neurodegenerative disorder and showed features consistent with normal aging (samples in this group were from healthy people age 65 and older).

A total of 173 brain tissue samples were examined.

Using a novel sequencing technique, the researchers sequenced — more than 5,000 times — 102 genes known to cause or put a person at risk of a neurodegenerative disease. Around 611,285 cells were sequenced.

The team reported 39 somatic mutations in 27 of the 54 examined brains, including both healthy (control) and diseased samples.

Somatic mutations are spontaneous genetic mutations (i.e., errors in DNA) acquired by a cell and occurring after conception. As cell division progresses during embryonic development, mutated cells will continue to be produced until the body that harbors those cells dies. But these somatic mutations cannot be passed to offspring because they do not occur in germ cell DNA, which are the cells that create sperm or egg.

Eighteen spontaneous mutations (56.4% of the total 39 detected “genetic errors”) were present in only one brain region — although in many cells there, while 17 others (43.6% of 39 mutations) occurred in more than one brain region.

Because the single region mutations occurred in numerous cells, it is highly probable that such DNA errors happened during embryo development, the scientists said.

Researchers then used a simplified mathematical model of neurodevelopment to help them understand their data. They inferred a mutation rate, simulated brain development using their model, and found that each individual tended to have 100,000 to 1 million disease-related mutated cells, suggesting that these mutations occur often in the general population.

Frame-shift mutations, i.e., an insertion or deletion of genetic material into the DNA sequence, in cell proliferation and differentiation disorder genes were detected in 40% of samples taken from people with Lewy body dementia, in comparison to 7% in those from the control group.

“These spelling errors arise in our DNA as cells divide, and could explain why so many people develop diseases such as dementia when the individual has no family history,” Chinnery said. “These mutations likely form when our brain develops before birth — in other words, they are sat there waiting to cause problems when we are older.

“Our discovery may also explain why no two cases of Alzheimer’s or Parkinson’s are the same,” he added. “Errors in the DNA in different patterns of brain cells may manifest as subtly different symptoms.”

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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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