Early Involvement of Caudate Brain Region Linked to Worse Prognosis in Parkinson’s Patients, Study Finds

caudate involvement

Almost half of people in the early stages of Parkinson’s disease already have signs of neurodegeneration in a brain region called the caudate, which was previously thought to affect mostly those at advanced disease stages, a study reports.

Early caudate involvement on both sides of the brain, as seen by DaTscan imaging of the brain, appeared to predict the risk for worse outcomes, including cognitive impairment, depression, and gait problems, over a four-year follow-up period.

These findings suggest that caudate involvement detected through DaTscan neuroimaging may serve as an early biomarker to identify patients at a greater risk of faster disease progression in the near future.

The study, “Clinical implications of early caudate dysfunction in Parkinson’s disease,” was published in the Journal of Neurology, Neurosurgery & Psychiatry.

Parkinson’s disease is believed to be caused by the impairment or death of dopamine-producing nerve cells (neurons) in a region of the brain called the substantia nigra, which controls the body’s balance and movement.

When the disease is established, or advanced, the degeneration of dopaminergic neurons and nerve fibers frequently extends to a brain region called the caudate nucleus. This region plays important roles in motor control as well as in various other non-motor tasks, such as learning and sleep.

In fact, the loss of dopaminergic function in this region is known to contribute to the hallmark symptoms of Parkinson’s including cognitive impairment, depression, sleep disorders, and gait problems.

Although less common, caudate dopaminergic dysfunction may also emerge in the early stages of the disease, in which case it could also contribute to the onset of non-motor symptoms. However, the frequency of this specific brain impairment in early Parkinson’s is unknown as are its clinical implications for patients.

To address this lack of knowledge, a team, led by researchers at the University of Milan in Italy and Newcastle University in England, investigated the prevalence of caudate dopaminergic dysfunction in people who were still in the very early stages of Parkinson’s.

By comparing the participants’ state at the beginning of the study and four years later, they also looked for associations between caudate involvement and an increased risk of disease progression.

They analyzed clinical data from 397 patients who had had a Parkinson’s diagnosis for two years or less, and were participating in the Parkinson’s Progression Markers Initiative (PPMI), an ongoing study attempting to identify biomarkers of disease progression. The team compared the collected clinical data from Parkinson’s patients with that of 177 healthy volunteers.

Caudate dysfunction was detected using 123I-FP-CIT single-photon emission computed tomography, commonly known as DaTscan. This is an imaging technique that depicts the levels of dopamine transporters in the brain that is often used to confirm a Parkinson’s diagnosis.

Based on DaTscan imaging data, the participants were divided into three groups: those who had no reduction of dopamine transporters, those who showed reduction in just one side of the brain, and those who had involvement of both sides of the brain.

Initial data showed that 51.6% of the patients had signs of normal caudate dopamine function, while 26% had caudate dopaminergic dysfunction on one side of the brain (unilateral), and 22.4% on both sides (bilateral).

Four years later, the patients who initially had bilateral caudate involvement were found to experience more frequent and worse cognitive impairment and depression, and more severe gait disability.

In general, after four years of follow-up, more patients showed a loss of dopaminergic nerve fibers in the caudate, compared with the study start, affecting 83.9% of patients (unilateral 22.5%, bilateral 61.4%).

“In this study, we have demonstrated a high frequency of early caudate dopaminergic dysfunction in patients with recently diagnosed [Parkinson’s disease],” the researchers wrote.

“Our study suggests that early bilateral caudate dopaminergic dysfunction is associated with an increased frequency of clinically significant depression and to worse depressive symptoms, regardless of age,” they added.

DaTscan parameters used to define the presence of early caudate dysfunction may be a “valid indicator of more rapid onset of such symptoms,” they said, which may help in “identifying patients at risk of clinical progression to cognitive impairment, depression, and gait problems in the near future.”

Assessment of caudate dopaminergic denervation may also assist clinicians in better predicting disease course at an early stage and identifying patients who may benefit the most from early, targeted disease-modifying therapies.

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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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Apathy and Depression Linked to Sleep Disorder in Parkinson’s Patients, Study Finds


Symptoms of apathy and depression are more frequent and severe in Parkinson’s patients with rapid eye movement sleep behavior disorder (RBD) than in patients without this disorder, according to a study.

Findings also showed that women with Parkinson’s and RBD are more likely to experience apathy than men.

The study, “Apathy in Parkinson’s disease with REM sleep behavior disorder,” was published in the Journal of the Neurological Sciences.

RBD affects up to half of Parkinson’s patients and often appears several years before motor symptoms. People with Parkinson’s and RBD typically experience more non-motor symptoms such as cognitive impairment, daytime sleepiness, and depression than those without RBD.

Apathy is very common in Parkinson’s patients and affects the treatment and long-term outcomes of the disease. Recent evidence showed a high prevalence of apathy in people with RBD and depression, but studies on the association between these disorders in Parkinson’s patients are still lacking.

Researchers at the University of Bern in Switzerland addressed this shortcoming by analyzing the motor function of 64 Parkinson’s patients, using the modified Hoehn & Yahr stage and the Unified Parkinson’s Disease Rating Scale (on and off dopaminergic medication), prior to deep brain stimulation from 2012 to 2016.

Non-motor assessments included the Starkstein apathy scale (SAS), the Hamilton depression rating scale, the Epworth sleepiness scale, and the mini-mental state examination of cognitive impairment. No patient had relevant cognitive deterioration or dementia.

Of the patients, 26 (40%) fulfilled the criteria for RBD (mean age of 62.6 years, Parkinson’s duration of 12.8 years), while 38 did not (mean age of 63 years, disease duration of 11.4 years). Motor function of the two groups only differed in the UPDRS part 2 score, related to daily living activities. This score was higher in patients with RBD when specifically analyzing the periods they were off medication.

Among the patients with RBD, 52% had apathy, defined as a score of 14 or higher on the SAS, while 50% had more symptoms of depression. In the group without RBD, apathy was observed in 42% of patients and depressive symptoms in 20% of them.

Patients with RBD had significantly higher mean apathy and depression scores, indicating greater severity, than those without this disorder. Higher apathy scores were especially seen in women. In contrast, the results of sleepiness and cognitive function were similar between the two groups.

“In [Parkinson’s], RBD is associated with isolated apathy and increased severity of depressive symptoms, independent of medication, motor and other non-motor symptoms,” the researchers wrote.

As for patients without depression, an increased apathy score was found in 53% of those with RBD and 29% of those without RBD. The data also showed that 58% of those with RBD and 64% of those without RBD had increased depressive symptoms but not an increased apathy score.

According to the researchers, this finding means that although their overlap is well-known, “apathy should not be considered as a mere symptom of depression.”

In the group with RBD, women showed more frequent and more severe apathy, as well as more frequent use of antidepressants than men, but these were not statistically significant. However, gender was the only independent predictor of apathy in the group with RBD, with women having a higher risk. No other gender difference was found.

This study suggests that patients with Parkinson’s and RBD “should receive targeted medical attention to improve diagnosis, monitoring and management of neuropsychiatric symptoms and their consequences,” the researchers concluded.

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New DBS Method Eases Both Cognitive and Motor Symptoms in Parkinson’s Patient, Study Shows

DBS patient expectations

A new approach to deep brain stimulation (DBS) was able to reduce both motor and cognitive impairments in a patient with Parkinson’s disease, a case study reports.

Described by the researchers in Spain who conducted the study, this alternative to conventional DBS involves a single electrode that is placed in each side of the brain, which is able to stimulate two different regions at the same time.

The study, “Simultaneous Stimulation of the Globus Pallidus Interna and the Nucleus Basalis of Meynert in the Parkinson-Dementia Syndrome,” was published in the journal Dementia and Geriatric Cognitive Disorders.

DBS is a type of surgery recommended for Parkinson’s patients who fail to respond to other medications. The procedure involves implanting a device that sends electrical signals produced by a battery to stimulate specific regions of the patient’s brain.

Although previous studies have shown that DBS can effectively reduce Parkinson’s motor symptoms, the same cannot be said regarding cognitive deficits, which may affect up to 60 percent of recently diagnosed patients.

“In fact, patients with dementia or significant cognitive impairment are often excluded from DBS studies … based on reports of irreversible cognitive worsening after DBS surgery in patients with preexisting cognitive impairment,” the researchers wrote.

Now, these researchers have explored the therapeutic potential of a new type of DBS that is able to target two brain regions simultaneously.

The single-case study focused on a 68-year-old patient with six years of clinical history, showing signs of mild cognitive impairment, who underwent DBS targeting two different regions of the brain with a single electrode placed on each hemisphere (half): the globus pallidus interna (GPi), to treat motor symptoms; and the nucleus basalis of Meynert (NBM), to treat cognitive deficits.

Two months after starting GPi stimulation, the patient started showing signs of motor improvement, reflected by a reduction of 61.37% in the Unified Parkinson’s Disease Rating Scale (UPDRS-III) score and in a performance improvement of 80% during the Up and Go test, compared with before the treatment. The UPDRS-III assesses the severity of motor symptoms, while the Up and Go test assesses mobility according to the time it takes an individual to rise from a chair, walk 3 meters, turn around, walk back to the chair, and sit down.

Moreover, the levodopa equivalent dose (a rough technique to compare different medications; LED) score decreased by 16.81% following GPi stimulation.

Motor improvement at two months was accompanied by a general decline in cognitive performance. However, minor cognitive improvements were found three months after the patient began receiving NBM stimulation together with GPi stimulation, namely in the capacity for abstraction, non-verbal memory (our visual memory system), verbal memory retrieval, and speed processing (the time it takes a person to do a mental task).

“The follow-up conducted 1 year after starting the combined GPi + NBM stimulation confirmed the improvement in UPDRS-III scores, along with a 20% reduction in LED compared to baseline. No visual side effects were recorded during the follow-up,” the researchers wrote.

“This approach showed no significant side effects and resulted in improvements in certain cognitive functions in a patient with baseline mild cognitive impairment, which would have excluded this patient from undergoing DBS under most current protocols. Further research is necessary before offering this surgical alternative to a wider range of patients,” they concluded.

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Genetic Variant Predetermines Risk of Cognitive Decline in Parkinson’s, Research Suggests

genetic variant

Researchers have found that Parkinson’s patients whose cognitive ability is intact, but who have a specific genetic variant, have significantly less gray matter in the regions of their brain that are related to dementia.

The study with that finding, “Reduced gray matter volume in cognitively preserved COMT 158Val/Val Parkinson’s disease patients and its association with cognitive decline,” was published in Brain Imaging and Behavior.

Several mutations in the COMT gene have been associated with the risk of developing Parkinson’s disease. This gene provides instructions for making catechol-O-methyltransferase (COMT), an enzyme that helps break down certain chemical messengers like dopamine.

The most common alteration in the DNA sequence that makes up the COMT gene is the Val158Met mutation in which a valine (Val) is replaced by a methionine (Met) at position 158. Val and Met are both amino acids, also known as the protein’s building blocks.

Every individual has two copies of each gene, one inherited from each parent. Therefore, a person can have two Val’s in the same position at both COMT gene copies (also known as the Val/Val genotype), a Val in one gene and a Met in the other (Val/Met genotype), or two Met’s (Met/Met genotype). Scientists use the word “genotype” to describe a person’s genetic constitution.

Changes in COMT’s molecular structure, lead to high (Val/Val), intermediate (Val/Met) and low (Met/Met) enzymatic activity.

The Val158Met mutation in the COMT gene has been associated with an increased risk of cognitive decline in Parkinson’s disease, particularly in people with greater COMT activity. When this happens, there is too much neurotransmitter degradation, thus leading to reduced levels of dopamine and affecting basic brain functions such as motor coordination and memory.

Evidence suggests a correlation between cognitive impairment, one of Parkinson’s non-motor features, and reduced gray matter volume.

The brain is composed of gray and white matter. The first consists of cell bodies — the control center of neurons — while the latter is made up of nerve cell projections, known as axons or fibers, connecting distinct parts of gray matter.

A Spanish team of researchers used magnetic resonance imaging (MRI), a non-invasive imaging technology, to investigate a possible structural brain compromise in Parkinson’s patients with highly active COMT activity that could explain their increased risk for subsequent cognitive impairment.

The study included 120 newly diagnosed Parkinson’s patients with normal cognition (who were not previously treated for the disease) and 48 healthy controls from the Parkinson’s Progression Markers Initiative database.

Results showed that there was a widespread, significant reduction in cerebral gray matter volume in patients with the Val/Val genotype. They observed alterations in the fronto-subcortical and posterior-cortical brain regions, where motor and cognitive functions originate.

Gray matter volume at some of the identified regions was associated with cognitive decline in a four-year follow-up period, suggesting that gray matter volume reduction during the early stages of disease predisposes Val/Val patients to cognitive impairment.

Nonetheless, gray matter volume analysis at one-year follow-up was not increased in Val/Val subjects, in comparison to Val/Met and Met/Met participants, indicating a somewhat stable atrophy in the Val/Val subset and that those brain changes might already be present prior to diagnosis.

The team believes their research “sparks the need to further characterize the association between a modified COMT enzymatic effect and a structural brain compromise in the early stages of [Parkinson’s disease].”

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US Study Shows Patterns of Prescription Errors for Dementia Therapies to Parkinson’s Patients

dementia prescription errors

Women and Hispanic patients with Parkinson’s disease, as well as those living in Southern and Midwestern U.S. states, are most often prescribed inappropriate dementia therapies, a nationwide study reveals.

The study, “Patterns of Dementia Treatment and Frank Prescribing Errors in Older Adults With Parkinson Disease,” appeared in the journal JAMA Neurology.

Cognitive impairment in Parkinson’s patients is a major reason behind their loss of independence, as well as nursing home placement and healthcare costs. About 1 in 4 Parkinson’s patients has objective cognitive impairment at the time of diagnosis, and dementia affects about 80-90% of patients by 12 years after diagnosis.

Despite the high incidence of cognitive impairment in Parkinson’s patients, there is little information on dementia medication use.

University of Pennsylvania researchers reviewed the clinical records of 268,407 Medicare beneficiaries with a Parkinson’s diagnosis who had 12 consecutive months of inpatient, outpatient, and prescription medicine coverage from January to December 2014. Medicare is the primary insurer for 97 percent of the U.S. population ages 65 years or older.

According to Medicare Services data, about 27.2% of the Parkinson’s patients included in the study had filled at least one prescription for a dementia medication in 2014. The most commonly prescribed therapy was Aricept (donepezil), followed by Namenda (memantine) and Exelon (rivastigmine), while Razadyne (galantamine) use was uncommon.

Women were found to be 15% less likely to use dementia medication than men. Black patients were 38% more likely and Hispanic patients 28% more likely to use these therapies than white patients, while Native Americans were about 38% less likely.

“Female sex was associated with lower odds of dementia medication use … Dementia medication use was positively associated with black and Hispanic race/ethnicity, and it was negatively associated with Native American,” the researchers wrote.

Use of a dementia medicine was associated with a dementia diagnosis, but also depression, hip or pelvic fracture, and stroke or transient ischemic attack.

Approximately 66.4% of patients were only prescribed a single dementia medicine during the year, while 26.7% had prescription fills for both Namenda and an acetylcholinesterase inhibitor (AChEI), most frequently Aricept or Exelon.

“Coadministration of a drug with high anticholinergic activity [such as Namenda] and an AChEI represents a frank prescribing error because these drugs have opposing pharmacologic effects,” the researchers wrote.

“In patients with Parkinson disease, who bear additional risks of cognitive impairment and vulnerability to anticholinergic activity, coprescribing of an ACHEI and a high-potency anticholinergic medication can be considered a never event because it is a medication error likely to contribute to disability,” they said.

Almost 45% of Medicare beneficiaries with Parkinson’s and a clinical diagnosis of dementia filled a prescription for a medication that could further worsen their cognitive impairment over the course of a single year.

The records revealed that black beneficiaries were 17% less likely to be prescribed both a high-potency anticholinergic agent and AChEI than white Parkinson’s patients. In contrast, Hispanics and women had an 11% and 30% increased chance of experiencing this so-called never event, defined as a serious medical error or occurrence that should never happen to a patient and can cause harm.

Dual prescriptions of an anticholinergic agent and AChEI were found to be more frequent among patients with secondary conditions, including depression, chronic obstructive pulmonary disease (COPD), hypertension, chronic kidney disease, diabetes, and heart failure.

Clusters of high prevalence of inappropriate prescribing were found in the Southern and Midwestern U.S. regions, while clusters of low prevalence of inappropriate dual-prescribing were reported in the Northwest and Northeast.

“We identified unique patterns of dementia medication use among individuals with Parkinson disease, along with racial/ethnic, sex, and geographic disparities in potentially inappropriate prescribing habits,” the researchers said.

Further studies are warranted to explore the potential contributing role of anticholinergic agents in the development of dementia among Parkinson’s patients.

“Future studies may take a clinical trial approach, in which high-potency anticholinergic medications are replaced with lower-potency alternatives, and the change in cognitive testing and cognitive trajectory are measured,” the researchers suggested.

Additionally, improvements in practitioner education may “lessen negative patient outcomes in the future,” they added.

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Poor Sense of Smell Evident in Parkinson’s Patients in Small Study, But Not Linked to Dementia

Olfactory deficits — a diminished sense of smell — affected 95% of Parkinson’s disease patients in a small study, but such problems did not appear to be linked to cognitive impairment or disease-related dementia.
The study, “Association between olfactory loss and cognitive deficits in Parkinson’s disease,” was published at the journal Clinical Neurology and Neurosurgery.
Previous research has suggested that a poor sense of smell is a non-motor symptom of Parkinson’s disease experienced by many patients — about 90% — during its initial and moderate stages.
Researchers have also found possible associations between olfactory dysfunction and a patient’s risk of developing dementia, with recent studies indicating a three times higher risk of cognitive deficits appearing in 10 years in these patients.
A research team in Brazil compared the cognitive and olfactory capacity of 42 Parkinson’s patients and 38 age- and sex-matched healthy volunteers.
Patients had lower cognitive scores compared to the control group, as determined by the Scales for Outcomes in Parkinson’s Disease-Cognition (SCOPA-Cog) and Mini-Mental State Examination (MMSE) tests. Thirty-four, or 81%, of them were diagnosed with dementia based on the International Parkinson and Movement Disorder Society criteria.
This high number of Parkinson’s dementia patients “can be partly explained by the fact that the study was carried out in a reference center for Parkinson’s disease treatment, where patients had longer disease duration and more complications,” the researchers said.
Patients’ sense of smell was assessed using the Sniffin’ Sticks Screening 12 Test, in which the participants are asked to identify each stick’s respective scent from among four options.

Based on the number of correct answers, the prevalence of olfactory dysfunction in Parkinson’s patients was 95.24% — 40 out of 42 patients were classified has having an impaired sense of smell.

Further analysis found no association between olfactory and cognitive impairment among patients, regardless of their age (although older patients had worse results — an expected finding as sense of smell is known to diminish with age, especially in men, the study noted). The only exception was in attention, the one cognitive domain that correlated with a loss or diminishment of olfactory abilities.
Among volunteers, cognitive and olfactory scores strongly correlated, both in the SCOPA-Cog and MMSE results.
A possible explanation for these results, the researchers said, could be a difficulty recognizing odors due to poor cognitive ability.

This mean a study limitation might be “the choice of the instrument to measure olfaction, because although olfaction can be evaluated in several ways (…) the Sniffin ‘Sticks Screening Test only evaluates odor identification,” the researchers wrote. “Because odor identification requires more cognitive processing and memory use than the other two ways of assessing smell (odor threshold and discrimination), it would be possible that cognitive impairment at the time olfaction was assessed affected the olfactory scores.”

Collectively, this study revealed that “patients with advanced Parkinson’s disease have cognitive and olfactory deficits more commonly than other elderly patients,” the researchers wrote.
But a link between olfactory deficit and the onset of Parkinson’s dementia could not be established. Further studies are necessary to assess sense of smell in a larger Parkinson’s population, and to

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Tiny Brain Bleeds Associated with Parkinson’s Disease Dementia, Study Reports

cerebral microbleeds, dementia

Tiny bleeds in the brain are associated with cognitive impairment in Parkinson’s disease and risk of Parkinson’s disease dementia (PDD), a Japanese study has found.

The research, “The presence of cerebral microbleeds is associated with cognitive impairment in Parkinson’s disease,” was published in the Journal of Neurological Sciences.

Cerebral microbleeds (CBMs) are small, chronic brain hemorrhages likely caused by structural abnormalities of the small vessels in the brain. CBMs are markers of small vessel disease frequently found in normal aging, as well as in patients with stroke and Alzheimer’s disease. These lesions are known promoters of cognitive decline in the elderly and are linked to poor prognosis in Alzheimer’s patients.

Cognitive impairment is one of Parkinson’s non-motor symptoms and, along with dementia, affects Parkinson’s prognosis. Other non-motor symptoms – including visual hallucinations, sleep problems, behavior disorders, and orthostatic hypotension (a decrease in blood pressure when standing up), as well as older age at onset — are considered risk factors for Parkinson’s cognitive decline.

The authors previously had shown that CBMs are common in Parkinson’s patients. Also, experimental studies reported that brief brain blood flow reduction promotes the aggregation of alpha-synuclein protein, a key player in Parkinson’s disease.

However, whether the presence of these lesions is a risk factor for cognitive impairment in patients with Parkinson’s was not clear.

Juntendo University researchers retrospectively analyzed a total of 124 clinically diagnosed Parkinson’s patients to determine the association between the presence of CBMs and cognitive decline. Both early-stage and advanced disease cases were included.

Twenty-one patients (16.9%) were diagnosed with PDD. Factors including gender, age, Hoehn and Yahr (H-Y) stage (a system used to assess the worsening of Parkinson’s symptoms) history of stroke, orthostatic hypotension (defined as a 20-mm Hg drop in systolic and/or a 10 mm Hg drop in diastolic blood pressure), systolic hypertension (systolic blood pressure equal to or higher than 140 mm Hg), specific cerebrovascular lesions, and the use of oral blood thinners. All significantly correlated with PDD.

Matching prior findings, abnormal nocturnal blood pressure — increasing or falling 10 to 20% — also was associated with PDD.

CBMs — defined by brain MRI as having a diameter of 2-10 mm — were observed more frequently in PDD patients than in those without dementia. This finding was maintained across different microbleeds’ types called deep or infratentorial (below the brain lobes) and strictly lobar (restricted to the brain lobes).

Also, both types of CBMs were associated with lower cognitive scores, as measured with the Mini-Mental State Examination (MMSE) and the Hasegawa dementia scale-revised. Patients with a strictly lobar type of microbleed scored lower on both scales than individuals with deep or infratentorial ones.

Patients with CBMs were older and had a higher (worse) H-Y stage than those without these lesions. They also showed more severe cerebrovascular lesions and higher prevalence of hypertension, diabetes mellitus, history of ischemic stroke, coronary artery disease, orthostatic hypotension, systolic hypertension, and use of oral blood thinners and anti-hypertensive medications.

Importantly, male gender, cerebrovascular lesions on MRI, and strictly lobar CMBs (but not deep and infratentorial) were risk factors for PDD.

“In conclusion, CMBs, especially strictly lobar type, are associated with cognitive decline and dementia in [Parkinson’s],” researchers wrote.

Amyloid plaques — typical in Alzheimer’s patients’ brains — are known contributors for cognitive decline in Parkinson’s and are more common in PDD patients than in those with Parkinson’s but not dementia. In fact, up to 50% of patients with PDD also may have an Alzheimer’s pathology.

“[O]ur data suggest that [Parkinson’s] cases with strictly lobar distribution of CMBs may have an underlying [Alzheimer’s] pathology and contribute to cognitive decline,” the scientists added.

However, the research team noted that future studies with larger patient groups are necessary to confirm these results.

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Aptinyx’s Investigational Parkinson’s Therapy NYX-458 Enters Phase 1 Clinical Testing

NYX-458 Parkinson's therapy

Aptinyx has launched a Phase 1 clinical trial of NYX-458, a potential treatment for cognitive impairment in Parkinson’s disease patients.

The randomized, double-blind, placebo-controlled trial will be conducted in roughly 62 healthy volunteers to evaluate the safety, tolerability, and pharmacokinetics of the compound. Pharmacokinetics refers to a drug’s absorption, bioavailability, distribution, metabolism, and excretion in the body.

Patients will receive both single and repeat dosing of NYX-458 at multiple dose levels to determine the optimal dosage for future Phase 2 studies. The company is planning studies to test the effectiveness of the investigational therapy next year.

“Based on the compelling preclinical evidence of NYX-458 in reversing cognitive impairment, we are excited to initiate this first-in-human study and advance NYX-458 as a potential treatment for this very common and highly limiting, but poorly treated, symptom of Parkinson’s disease,” Torsten Madsen, MD, PhD, chief medical officer of Aptinyx, said in a press release.

NYX-458 is a small molecule therapy that functions by regulating the activity of N-methyl-D-aspartate (NMDA) receptors, which are found in nerve cells, enhancing synaptic plasticity and improving nerve cell communication. Synapses are the junctions between two nerve cells that allow them to communicate; synaptic plasticity refers to the ability of synapses to strengthen or weaken over time.

Synaptic plasticity contributes to learning, memory, and cognition, all of which are often impaired in Parkinson’s patients.

Earlier this year, Aptinyx presented positive preclinical data of NYX-458 during the 2018 Advances in Alzheimer’s and Parkinson’s Therapies Focus Meeting in Torino, Italy.

The study, which was conducted in a non-human primate model of Parkinson’s disease, showed that NYX-458 significantly increased attention, improved cognitive flexibility, and enhanced working memory as quickly as two hours after the administration of a single oral dose. Those effects were maintained for up to three weeks. No major safety or tolerability issues were observed.

“… NYX-458 has the potential to be a meaningful therapy for patients suffering from some of the most devastating symptoms of Parkinson’s disease,” Cassia Cearley, PhD, vice president of research at Aptinyx, said in a press release at the time. “These results in a relevant and highly translatable model warrant the advancement of NYX-458 into clinical studies.”

So far, Aptinyx’s chemistry and discovery platform has generated three therapeutic candidates, NYX-2925, NYX-783, and NYX-458, currently in clinical development for the treatment of various nervous system disorders. This platform is unique in that it discovers compounds that work to regulate — rather than block or over-activate — NMDA receptors to enhance synaptic plasticity, which is the foundation of nerve cell communication.

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Psychosis in Parkinson’s Linked to Volume Changes in Specific Area of Brain, Study Says

psychosis in Parkinson's

Psychosis and cognitive impairment in patients with Parkinson’s disease may be linked to structural changes in the brain, namely a decrease in volume of an area that controls memory formation, a study suggests.

The study, “Hippocampal subfield atrophy in patients with Parkinson’s disease and psychosis,” was published in the Journal of Neural Transmission.

Psychosis, which usually manifests as visual hallucinations, is one of the most frequently observed non-motor symptoms of Parkinson’s disease.

More than 50 percent of Parkinson’s patients will experience psychosis in their lifetimes, and the condition is associated with poor quality of life and more use of healthcare resources.

The causes underlying psychosis in Parkinson’s disease remain unclear, but some studies suggest it may be linked to structural and functional alterations of the hippocampus, a brain region that plays a key role in memory formation.

Using magnetic resonance imaging (MRI), researchers analyzed the hippocampus of 51 Parkinson’s patients without psychosis, 42 Parkinson’s patients with psychosis, and 48 healthy people matched by age, gender, and education, used as controls.

Patients were recruited from the National Institute of Mental Health and Neurosciences in Bangalore, India.

Additional parameters analyzed included participants’ overall cognitive performance, measured using the Montreal Cognitive Assessment Scale (MoCA), and frontal executive functions — the skills a person uses to plan, organize and complete tasks — evaluated using the frontal assessment battery (FAB), which assesses the brain’s frontal lobe function.

Overall cognitive performance was significantly higher in healthy controls than in Parkinson’s patients both with and without psychosis. There were no significant differences in cognition between the Parkinson’s patients, regardless of whether they had psychosis or not.

FAB scores were also significantly lower in both groups of Parkinson’s patients than controls, highlighting an impairment in executive functions in patients both with and without psychosis.

Researchers observed that the overall volume of the hippocampus was reduced in Parkinson’s patients with psychosis compared with healthy controls, and that the volumes of different subzones in the hippocampus of these patients correlated with psychosis severity and cognitive functions.

However, Parkinson’s patients with psychosis had increased volume of a specific region within the hippocampus called the hippocampal fissure. The higher the volume in this area, the lower the capacity of visual memory and visuospatial functions.

Mouse studies have previously demonstrated that an increase in hippocampal fissure volume is highly correlated with a decrease in overall hippocampal volume, and can be considered a radiological hallmark of ongoing brain atrophy.

“We demonstrated that the trajectory of psychosis severity could be mapped using hippocampal subfield volumes,” the researchers wrote.

These results support the involvement of specific hippocampal regions in psychosis and cognitive impairment in Parkinson’s disease.

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Source: Parkinson's News Today