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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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Tremor-Dominant Parkinson’s Linked to Less Severe Cognitive Decline, Study Says

motor symptoms

Specific motor symptoms in Parkinson’s disease have a corresponding cognitive profile, with the tremor-dominant type being associated with less severe cognitive decline, a study reports.

The study, “Cognitive decline in Parkinson’s disease: the impact of the motor phenotype on cognition,” was published in the Journal of Neurology, Neurosurgery, and Psychiatry.

Parkinson’s disease is a multisystem neurodegenerative disorder with motor and non-motor features. Rest tremor, slowness of movement (bradykinesia), rigidity, and impairment of posture, balance, and gait are among the motor symptoms and signs, while cognitive decline is a recognized non-motor complication with significant clinical impact.

“There is evidence that approximately 30%–40% of patients with PD [Parkinson’s disease] develop cognitive deficits and may get dementia, starting with mild cognitive impairment and evolving to a more generalized dysfunction of cognition,” the researchers wrote.

Parkinson’s disease has three subtypes of motor symptoms:

  • Tremor-dominant, meaning patients experience more tremor than any other motor feature.
  • Akinetic-rigid, where patients exhibit slowness of movement accompanied by muscle stiffness and postural instability plus gait difficulty.
  • Not-determined, in which patients show mixed symptoms.

“Akinetic-rigid patients have previously been associated with faster cognitive decline, greater risk of dementia and higher sensitivity for depression,” the researchers noted. Scientists believe this is dependent on the affected brain circuit.

Evidence suggests a significant link between compromised working memory and akinetic-rigid patients. Working memory is the type of memory that holds temporary information needed only to accomplish an immediate task. For example, when putting a new contact into a phone, a person temporarily memorizes the digits in the phone number until he or she is done with that task.

Despite the need for a detailed understanding of Parkinson’s motor subtypes, available studies demonstrate inconsistent results about the relation of cognitive function and implemented motor subclassifications.

To address these discrepancies, researchers from RWTH Aachen University in Germany set out to identify distinct cognitive profiles among Parkinson’s patients according to motor subtype. They also examined mental performance within each cognitive diagnosis group, i.e., patients with a normal cognitive profile, mild cognitive impairment, and dementia.

They analyzed data from the DEMPARK/LANDSCAPE study, a multicenter, longitudinal, observational, German cohort study of 538 Parkinson’s patients (ages 50-80 years old), and organized it by motor subtype and cognitive pattern.

In the DEMPARK/LANDSCAPE study, patients were assessed by a series of motor, cognitive, depression, and health status-related questionnaires/scales.

For further cognitive assessment, researchers tested verbal memory, non-verbal memory, attention, executive function (meaning “behavior control,” which includes inhibition, memory, attention, flexibility, planning, and problem-solving), visuospatial function (ability to process and interpret visual information about an object’s position in space), and language skills.

Data analysis showed that compared with tremor-dominant patients, akinetic-rigid patients performed significantly worse in executive functions, including working memory, card sorting, visuospatial skills, and the ability to mentally select and pronounce words meeting certain test-related constraints.

Neuropsychological test scores revealed that executive function and attention were negatively correlated with non-tremor motor scores, which is consistent with previous studies finding that motor symptoms influence cognition.

Parkinson’s patients with the not-determined subtype were three times more likely to develop mild cognitive impairment than tremor-dominant subjects, and twice as likely as akinetic-rigid patients.

In addition, akinetic-rigid patients were eight times more likely to develop dementia than tremor-dominant participants.

“The present results show that akinetic-rigid patients undergo greater cognitive decline in several cognitive domains compared with [tremor-dominant PD] patients, calling for early diagnosis in particular in the higher risk group and individualized therapy interventions at the earliest point,” the researchers concluded.

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Structural Changes in Brain Predict Cognitive Decline in Parkinson’s Patients, Study Suggests

Parkinson's cognitive decline

Structural changes in a specific region of the brain can predict the onset of cognitive impairment in Parkinson’s patients who have not yet developed dementia, according to a recent British study.

The study, “Nucleus basalis of Meynert degeneration precedes and predicts cognitive impairment in Parkinson’s disease,” was published in the journal Brain.

A brain region called the nucleus basalis of Meynert has been identified as the primary source of acetylcholine — a brain chemical important for cognitive function development, including memory, learning, and concentration abilities.

Cognitive impairment is highly prevalent in Parkinson’s disease, with approximately 80 percent of patients eventually developing dementia during the course of their illness. It is one of the most clinically relevant symptoms of the disease, and causes an increased risk of mortality and significant reduction in quality of life.

Studies have demonstrated that the structure of the nucleus basalis of Meynert appears to be more damaged in Parkinson’s patients with cognitive impairment. However, so far, there are no reliable predictors of dementia in Parkinson’s, and the mechanisms behind the development of cognitive impairment remain unclear.

King’s College London researchers hypothesized that structural changes in this specific brain region could be behind cognitive impairment in patients with Parkinson’s disease, and could predict the development of cognitive impairment. To test this, the team compared magnetic resonance imaging (MRI) data from Parkinson’s patients with and without cognitive impairment.

A total of 304 Parkinson’s patients and 167 healthy people in a control group were included in the study. The participants’ cognitive status was assessed at the start and then every six months for 36 months, or until a patient developed cognitive impairment.

No brain anatomy differences were observed between Parkinson’s patients and the control group. However, cognitively impaired patients had higher rates of neuronal loss within the nucleus basalis of Meynert than non-demented patients with Parkinson’s.

Damage to this brain region “was predictive for developing cognitive impairment in cognitively intact patients with Parkinson’s disease, independent of other clinical and non-clinical markers of the disease,” the authors wrote.

The team also analyzed the anatomy of other cognitive function-related brain centers, but structural and microstructural changes to those regions did not precede clinical onset of cognitive impairment.

Researchers concluded that “degeneration of the nucleus basalis of Meynert precedes and predicts the onset of cognitive impairment, and might be used in a clinical setting as a reliable biomarker to stratify patients at higher risk of cognitive decline.”

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Source: Parkinson's News Today

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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Source: Parkinson's News Today