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Cellular Location of Neuroprotective Protein Associated with Parkinson’s Disease Development, Study Finds

Nilotinib Phase 2 trial

Toxic protein aggregates called Lewy bodies sequestrate a protein that is usually found in the cell nucleus and known to protect against neurodegeneration, and change in this protein’s location contributes to the mechanisms underlying Parkinson’s disease, researchers report.

The study, “Loss of nuclear REST/NRSF in aged-dopaminergic neurons in Parkinson’s disease patients,” was published in Neuroscience Letters.

Aging is a primary risk factor for Parkinson’s disease as age-related changes in cellular function predispose people to the development of this neurodegenerative disorder.

Evidence suggests a close relationship between neuronal death and toxic protein inclusions, such as Lewy bodies — clumps of alpha-synuclein protein. However, the exact mechanism of how these aggregates result in disease remains to be understood.

“It has been reported that repressor element-1 silencing transcription factor, (also known as) neuron-restrictive silencer factor (REST/NRSF) is induced in the nuclei of aged neurons, preserves neuronal function, and protects against neurodegeneration during aging through the repression of cell death-inducing genes,” the researchers wrote.

Studies have shown that REST expression is decreased in Alzheimer’s disease, but little is known about its role in Parkinson’s disease.

Therefore, researchers from Juntendo University in Japan set to identify the neuroprotective functions of REST in aging and the brains of Parkinson’s disease patients.

The team used post-mortem brain samples of normal aging people (controls), and Parkinson’s or dementia with Lewy bodies patients, and looked at different areas to determine where REST was located within neurons.

In a normal aging (more than 72 years old) brain, REST was present in the nucleus and cytosol (the fluid found inside cells) of dopaminergic neurons present in the substantia nigra — a midbrain area important for muscle control.

This was not the case in the middle-aged brains (age 47 and 61 years), where REST was not observed in the nucleus, and there was a small amount of cytosolic accumulation, suggesting that nuclear entry of REST is dependent on the cellular aging process.

In contrast to healthy controls, REST expression was decreased in patients with Parkinson’s disease and dementia with Lewy bodies, both in the nucleus and cytosol of dopaminergic substantia nigra neurons and cortical neurons. Instead, REST was strongly detected within Lewy bodies.

To dissemble dysfunctional proteins, neurons use two major cellular pathways: the ubiquitin-proteasome system, where short-lived proteins in the cytoplasm and nucleus are degraded by a complex called the proteasome; and the autophagy-lysosome pathway, which digests long-lived proteins and abnormal cellular structures, including mitochondria, the cell’s powerhouse.

The proteasome is a tiny, barrel-shaped cellular structure that degrades toxic non-functional proteins that have been molecularly tagged for destruction.

Disease-related protein aggregates contain ubiquitinated proteins (proteins that have been “tagged” for degradation), and p62 — a molecular receptor that recognizes and shuttles ubiquitinated proteins for degradation.

Researchers wanted to understand whether REST interacted with ubiquitinated protein aggregates. Therefore, they investigated the transcription factor’s location in mouse brain cells that were either normal or were genetically engineered to lack the ability to perform protein degradation (autophagy) specifically in dopaminergic neurons.

In the substantia nigra of normal aging healthy mice (12 months of age), there was no detectable interaction between REST and p62, while in animals with a dysfunctional protein degradation pathway, REST was found in p62-positive aggregates within the cytoplasm. This suggests that REST is incorporated into cytoplasmic aggregates that accumulate as a consequence of autophagy dysfunction.

Therefore, REST aggregating with p62 suggests that it is part of a lesion associated with Lewy body formation.

Scientists then tested if the accumulation of ubiquitinated proteins induced REST gene expression in a human neuroblastoma (a rare type of cancer affecting the nervous system) cell line. Results showed that REST accumulated (was not degraded) in the presence of an autophagy inhibitor called MG132 — which blocks neuronal molecule-degradation systems. However, REST did not accumulate upon the addition of a proteasome-specific inhibitor, called lactacystin, which indicates that REST is dissembled via the autophagy-lysosome pathway.

When researchers added rotenone (a pesticide that inhibits the function of mitochondria) to neurons, REST accumulation increased.

“As rotenone is a possible Parkinson-causing agent, loss of neuronal REST accumulation in aged-neurons may relate to the PD pathology (the typical behaviour of a disease),” the researchers said.

Nuclear accumulation of REST “occurs as a normal aging process and Lewy pathology disturbs the process in dopaminergic neurons by sequestering REST. The alteration of neuronal aging processes including the loss of REST in neurons may associate with the PD pathogenesis,” they concluded.

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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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Specific Biomarkers May Help to Distinguish Parkinson’s Dementia from Dementia with Lewy Bodies

biomarkers, dementia study

The levels of specific protein biomarkers in the cerebrospinal fluid (CSF) — the liquid surrounding the brain and spinal cord — can distinguish patients with Parkinson’s disease dementia (PDD) from those with dementia with Lewy bodies (DLB) regardless of dementia stage, according to a new study.

The research, “Cerebrospinal fluid markers analysis in the differential diagnosis of dementia with Lewy bodies and Parkinson’s disease dementia,” appeared in the journal European Archives of Psychiatry and Clinical Neuroscience.

Brain protein clumps known as Lewy bodies are characteristic of both Parkinson’s and DLB.

Current practice gives a DLB diagnosis if dementia occurs before or during the first year of parkinsonism, a general term for neurological disorders that cause movement problems similar to those of Parkinson’s patients.

As such, a follow-up is essential to differentiate between PDD and DLB. However, the overlap of clinical symptoms and the difficulty in establishing when specific symptoms start make this distinction challenging and impacts treatment.

A percentage of DLB cases share a varying extent of pathological features with Alzheimer’s. But, unlike in that disease, no specific CSF biomarkers  have been validated for DLB and PDD. Researchers, for this reason, assessed the diagnostic potential of widely accepted CSF biomarkers across dementia stages to differentiate between DLB and PDD.

A total of 136 patients, all being treated at University Medical Center, Göttingen, Germany, underwent routine laboratory testing and a spinal tap to collect CSF. Cognitive examinations were preformed using the Mini-Mental State Exam (MMSE), and 65% of these patients were also tested with the Montreal Cognitive Assessment (MoCA), and the Clinical Dementia Rating (CDR).

The group included 51 people (31 men) with a diagnosis of probable DLB — 6 later confirmed — 53 with Parkinson’s, and 32 who were cognitively intact. Thirty-one of the Parkinson’s patients met the criteria for PDD (16 women and 15 men). Patients exhibiting dementia were classified as mild, moderate or severe.

CSF samples were tested for the proteins amyloid-beta1–42, tau, phoshorylated tau (a modified form of the tau protein), neuron-specific enolase (NSE) — a predictor of severity and neurobehavioral outcome after acute stroke, and implicated in Alzheimer’s — and S100B, a marker of brain damage. Of note, both amyloid-beta and phoshorylated tau form clumps in the brains of Alzheimer’s and Parkinson’s patients.

Levels of tau and amyloid-beta1–42, as well as the phosphorylated tau/total tau ratio were helpful in distinguishing between DLB and Parkinson’s patients with or without dementia.

Specifically, tau levels were higher in DLB than in Parkinson’s patients regardless of cognitive status, and were also higher in Parkinson’s patients with dementia than those without it.

DLB patients had lower levels of both amyloid-beta1–42 and phosphorylated tau/total tau ratio than did Parkinson’s dementia patients. This ratio was lower in DLB patients with mild and moderate dementia.

Levels of tau and phosphorylated tau protein in patients’ CSF reflected the severity of dementia in both DLB and PDD patients. Tau ratio enabled a distinction between Parkinson’s patients with mild and moderate dementia, and was lower in those with severe dementia than those with mild dementia.

Lower levels of amyloid-beta1–42 correlated with a rapid disease course in DLB but not in PDD. Both DLB and Parkinson’s patients with dementia showed elevated levels of S100B in comparison to healthy controls — indicating brain damage.

For both DLB and PDD, patients with less than a year of disease duration showed a trend toward higher tau, phosphorylated tau and NSE as opposed to lower amyloid-beta1–42  when compared to those whose disease had been diagnosed earlier.

Nevertheless, only values for amyloid-beta1–42 were lower in DLB patients whose dementia was confirmed less than one year after their primary diagnosis, compared to those diagnosed with PDD.

“These results have clinical relevance by suggesting that the descent of CSF [amyloid-beta1–42] values mainly in rapid disease course might have a prognostic significance,” the researchers wrote.

“[W]e conclude that CSF profile with the appropriate clinical context could be effective in distinguishing DLB from PDD patients, regardless of the severity of dementia,” they added.

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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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Researchers Identify New Gene Associated with Parkinson’s Disease, Dementia

Parkinson's gene

Mutations in the LRP10 gene are associated with the development of neurodegenerative diseases with Lewy bodies formation, such as Parkinson’s disease, Parkinson’s dementia and dementia with Lewy bodies, according to a recent study.

The study, “LRP10 genetic variants in familial Parkinson’s disease and dementia with Lewy bodies: a genome-wide linkage and sequencing study,” was published in The Lancet Neurology.

Abnormal deposits of the protein alpha-synuclein in the brain results in the formation of Lewy bodies and, eventually, nerve cell death. Lewy body formation affects chemicals in the brain whose changes can lead to Parkinson’s disease, Parkinson’s dementia, and dementia with Lewy bodies.

Mutations in specific genes — namely SNCA and LRRK2 — have been linked with inherited forms of these diseases. However, most patients do not have mutations in these genes. This suggests that additional genes may be responsible for Lewy bodies formation in these neurodegenerative disorders.

Several international researchers in collaboration with the International Parkinsonism Genetics Network analyzed patients’ data from clinical centers in Netherlands, Italy, Taiwan, Portugal, Brazil, the U.K., and Sweden.

By analyzing the genome (the total genetic material of an organism) of 10 relatives from an Italian family with a history of familial Parkinson’s disease and no mutations in known disease-causative genes, LRP10 was revealed as a potential culprit associated with the disease.

This gene was analyzed in 660 unrelated individuals diagnosed with Parkinson’s disease, Parkinson’s disease dementia or dementia with Lewy bodies from centers in those seven countries, and in 645 individuals with no indication of neurodegenerative diseases as a control group.

This analysis identified eight additional LRP10 mutations (in eight distinct patients) that potentially could be associated with these diseases.

When studying brain samples (autopsy-derived) from three patients with different LRP10 mutations, the researchers observed an elevated presence of Lewy bodies, strengthening the link between LRP10 mutations and the generation of these detrimental structures.

Three of the eight mutations severely impaired the production of the LRP10 protein, four affected protein stability, and two affected protein localization, suggesting that impaired LRP10 function may be a common mechanism behind the development of these diseases.

The LRP10 gene gives origin to the low-density lipoprotein receptor-related protein 10 (LRP10), which is involved in the cellular uptake of fat molecules.

LRP10 was found to localize in vesicle-like structures associated with proteins already known to be involved with alpha-synuclein accumulation and Parkinson’s disease, again stressing its involvement in Lewy body-associated diseases.

“Our work shows that LRP10 variants are implicated in Parkinson’s disease, Parkinson’s disease dementia, and dementia with Lewy bodies, and are associated with a severe burden of Lewy pathology [disease] in the brain,” researchers wrote.

Additional studies on the LRP10 protein function and its interaction with other proteins may potentially point to new biomarkers and therapeutic targets of these neurodegenerative diseases.

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Enzyme Tied to Inflammation and Progression in Parkinson’s May Hold Key to Treatment, Study Says

Parkinson's study

Blocking an enzyme associated with inflammation and disease progression in Parkinson’s patients may by a promising way of  treating this neurodegenerative disorder, new research suggests.

The study, “Soluble epoxide hydrolase plays a key role in the pathogenesis of Parkinson’s disease,” was published in the journal Proceedings of the National Academy of Sciences (PNAS).

Inflammation, impaired mitochondria (the cell’s power plants) and oxidative stress are know to exist in affected brain regions of Parkinson’s patients.

Epoxy fatty acids (EpFAs) — molecules produced from the oxidation of unsaturated fatty acids — have shown potent anti-inflammatory properties in animal models. Inhibiting the enzyme that breaks down these compounds, called soluble epoxide hydrolase (sEH), further enhances their beneficial effects.

Previous research has also shown that sEH plays a key role in depressive symptoms reported in Parkinson’s patients.

Using mouse models of the disease, researchers evaluated the potential of either inhibiting or genetically deleting sEH —  specifically in the striatum, the brain region involved in Parkinson’s disease. They also investigated sEH protein levels in postmortem brain samples of patients with Lewy body dementia, a progressive dementia related to Alzheimer’s. A similar dementia can afflict Parkinson’s patients.

Repeated oral administration of TTPU — an sEH inhibitor — improved levels of dopamine, a neurotransmitter, and associated metabolites in mice.

Deleting the gene that codes for sEH also protected the brains of these mice against induced neurotoxicity, while increasing  sEH production had the opposite effect.

Higher sEH activity was observed in the brains of mice models of Parkinson’s, specifically in the striatum, and levels of this enzyme positively correlated with those of a specific form of the protein alpha-synuclein, which is the main component of Lewy bodies in Parkinson’s and the dementia patients.

In both Parkinson’s mice and the dementia patients, sEH levels in the striatum were higher than in healthy controls.

The team next tested pluripotent stem cells — able to generate almost any cell type — derived from a patient carrying PARK2, one of the familial forms of Parkinson’s and caused by a mutation in the PRKN gene.

Treating these stem cell-derived neurons with TPPU prevented the loss of domaninergic cells. Levels of sEH messenger RNA, which contains the genetic information to produce the sEH protein, were also seen to be higher in the patient stem cell-derived neurons than in healthy controls.

“Collectively, these findings suggest that sEH plays a key role in the pathogenesis of [Parkinson’s] and that sEH inhibitors may prove to be promising prophylactic or therapeutic drugs,” the researchers wrote.

They added that, although the findings in the familial Parkinson’s case warrant additional studies in other familial or sporadic patients, transplanted human stem cells may be a promising way of better understanding disease mechanisms and its treatment.

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Synaptic Proteins Linked to Parkinson’s Could Aid in Early Intervention, Study Says

synaptic proteins

Key proteins involved in neuron communication are potential targets that could aid in early diagnosis and prediction of disease progression in patients with different types of dementias, including Parkinson’s disease, a study suggests.

The study, “Synaptic markers of cognitive decline in neurodegenerative diseases: a proteomic approach,” was published in the journal Brain.

Specific synaptic proteins, which are involved in neuron-to-neuron communication, were identified and linked to cognitive decline associated with Parkinson’s, Alzheimer’s, and dementia with Lewy bodies.

Loss of synaptic contact is a a common finding in the brains of individuals with Alzheimer’s disease. Synaptic dysfunction also occurs in Parkinson’s and dementia with Lewy bodies, according to studies.

Though early cognitive deficits are related to memory, decline is seen in all cognitive areas as neurodegenerative diseases progress.

Researchers from the Karolinska Institutet in Sweden analyzed the protein content of the prefrontal cortex of 32 post-mortem human brains of patients with Alzheimer’s disease, Parkinson’s disease with dementia, dementia with Lewy bodies, and older adults without dementia.

They looked specifically at proteins in the prefrontal cortex because of its role in cognition and executive functions (reasoning and decision-making) in all three diseases.

This was the first detailed quantitative protein analysis that focused on synaptic protein characterization of Alzheimer’s, Parkinson’s and dementia with Lewy bodies brains.

A total of 10,325 proteins were identified, 851 of which were synaptic proteins.

Researchers detected a pattern of protein loss in the area where electric nerve impulses are transmitted between two nerve cells across all three neurological disorders. Significant changes in the levels of 25 synaptic proteins were observed in all dementia groups.

Cognitive impairment before death and the rate of cognitive decline also closely correlated with the loss of five key synaptic proteins (SNAP47, SYBU, LRFN2, SV2C and GRIA3).

The team was able to successfully differentiate not only the distinct types of dementia in the demented samples, but also dementia samples from healthy controls.

“Besides differentiating Parkinson’s disease dementia, dementia with Lewy bodies, and Alzheimer’s disease from controls with high sensitivity and specificity, synaptic proteins also reliably discriminated Parkinson’s disease dementia from Alzheimer’s disease patients,” the researchers wrote.

“Our findings suggest that particular pre- and postsynaptic proteins have an important predictive and discriminative molecular fingerprint in neurodegenerative diseases and represent potential targets for early disease intervention, such as synaptic regeneration,” Erika Bereczki, PhD, lead author of the publication, said in a press release. Bereczki is a researcher at the Department of Neurobiology, Care Sciences and Society, Karolinska Institutet.

“Our results suggest shared mechanisms, with major implications for prognostic and diagnostic marker development as well as advancing future therapeutic interventions for improving the disease course. This places synaptic dysfunction and repair approaches in the spotlight of attention, especially since the therapeutic intervention window for synaptic repair and regeneration is longer than the recent toxin-clearance approaches,” she said.

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Cognitive Rehabilitation Improves Dementia Patients’ Goal Attainment, Study Shows

Parkinson's-related goals study

Goal-oriented cognitive rehabilitation was better than standard treatment or relaxation therapy at helping dementia patients achieve goals, a study reported.

It also led to patients getting more satisfaction from attaining goals, researchers said. And it led to caregivers reporting less stress and a better quality of life. The study was based on patients’ and caregivers’ self-reports.

The types of dementia the patients had were associated either with Parkinson’s disease or Lewy bodies, researchers said.

Their study, “Goal-orientated cognitive rehabilitation for dementias associated with Parkinson’s disease―A pilot randomised controlled trial,” appeared in the International Journal of Geriatric Psychiatry.

The main objective of the study was to assess the appropriateness and feasibility of goal-oriented cognitive rehabilitation for people with Parkinson’s-related dementia.

In goal-oriented cognitive rehabilitation, people with dementia and their families work together with a health professional to identify needs and goals, then try to achieve the goals.

The study included 29 people with dementia associated with Parkinson’s or with Lewy bodies and 26 caregivers.  After the patients set goals, they were randomized into three groups.

Ten received goal-focused cognitive rehabilitation, 10 others relaxation therapy, and nine standard treatment.

Cognitive rehabilitation occurred in eight weekly one-hour sessions with a therapist. Participants were given strategies for overcoming difficulties in planning and retaining information.

Relaxation therapy, also given in one-hour sessions for eight weeks, taught participants muscle relaxation and breathing exercises.

Participants in both groups were encouraged to practice their strategies between sessions with the help of their caregivers.

The study’s primary objective was to see if goal-oriented cognitive rehabilitation could improve patients’ ability to achieve goals and their satisfaction attaining goals than standard treatment.

One set of secondary objectives involved patients and another set caregivers. The patient set included seeing whether cognitive rehabilitation could improve patients’ mood, cognition, overall health, quality of life, and daily functioning. The caregiver set included seeing whether patients’ cognitive rehabilitation could reduce caregivers’ stress and improve their quality of life.

Researchers received patient and caregiver assessments at two and six months after the start of the study.

Two months after the patients set goals, the cognitive rehabilitation group reported more success achieving goals and more satisfaction doing so than the other groups. Another finding was that the relaxation therapy group reported better goal-attainment success and satisfaction than those in the standard treatment group.

At six months, cognitive rehabilitation continued to outperform standard treatment and relaxation therapy, although the difference was not as great as at two months.

Patients’ ability to achieve secondary objectives varied between the two-month and six-month assessments. At two months, cognitive rehabilitation did a better job than standard treatment and relaxation therapy in maintaining or improving patients’ mood and self-efficacy, or the feeling they could  achieve a goal. Those caring for cognitive rehabilitation patients reported that the quality of their own life had improved.

At six months, cognitive rehabilitation patients reported less delay in recalling information, better overall health, and better quality of life. Those caring for cognitive rehabilitation patients reported less stress, better overall health, and better quality of life than those caring for patients receiving standard treatment.

The results prompted researchers to suggest that goal-oriented cognitive rehabilitation is an effective treatment for dementia associated with Parkinson’s.

“Cognitive rehabilitation is feasible and potentially effective for dementias associated with Parkinson’s disease,” they wrote.

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Axovant’s Parkinson’s Therapy Shows Promise but Alzheimer’s Candidate Falls Short, Phase 2 Trials Show

Promsing Parkinson's therapy

An Axovant Sciences therapy for Parkinson’s disease showed signs of effectiveness, but an Alzheimer’s treatment did not, according to separate Phase 2 clinical trials.

Nelotanserin, the therapy candidate for Parkinson’s disease dementia (PDD) associated with hallucinations and for Dementia with Lewy Bodies (DLB), appeared safe as well as displaying signs of effectiveness, according to a Phase 2 trial (NCT02871427).

Meanwhile, intepirdine, a therapy candidate for Alzheimer’s and DLB, failed to meet its objectives in the Phase 2b HEADWAY trial (NCT02669433) and a pilot Phase 2 study (NCT02910102) that focused on walking and balance.

In the HEADWAY trial, 24-week administration of 35 mg or 70 mg of intepirdine in DLB patients did not produce statistically significant improvements in their movement, cognitive, and global functions, in comparison with placebo-treated patients.

Intepirdine has been well tolerated in all of its studies. But the poor effectiveness results did not come as a surprise. That’s because Axovant announced last year that the Phase 3 MINDSET study (NCT02585934) showed that intepirdine failed to help mild-to-moderate Alzheimer’s patients who were receiving background donepezil therapy.

Concerning the impact of intepirdine in dementia patients with gait and balance problems, 35 mg of intepirdine failed to improve gait speed.

“Based on the totality of intepirdine data to date, there is no evidence to support its further development,” David Hung, chief executive officer of Axovant, said in a news release.

In the case of nelotanserin, researchers looked at the safety of the drug in DLB and PDD patients experiencing visual hallucinations in a pilot Phase 2 study.

Preliminary results revealed nelotanserin seemed to decrease dementia progression in Parkinson’s patients.

Now, when researchers looked at 19 of the DLB patients in the Phase 2 hallucination trial, they reported that nelotanserin improved their movement scores on the Unified Parkinson’s Disease Rating Scale (UPDRS) by 4 points.

After seeing the data, the team analyzed a subset of patients who scored 8 or more, an indication of more severe psychotic symptoms, in the Scale for the Assessment of Positive Symptoms — Parkinson’s Disease (SAPS-PD).

They found that 40 mg of nelotanserin for two weeks, followed by 80 mg for two weeks, resulted in a 1.21-point improvement in SAPS-PD.

After these positive results, “we intend to discuss a larger confirmatory nelotanserin study with the FDA that is focused on DLB patients with motor deficits and more severe baseline psychotic symptoms,” Hung said. “Separately, we will be working with Roivant to build our pipeline to develop other new therapies for patients with neurological conditions who so desperately need them.”

In future trials, Axovant said it may also analyze nelotanserin’s effect on DLB and PDD psychotic symptoms.

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