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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Brain Changes Might Predict Parkinson’s Mild Cognitive Impairment

Mild cognitive impairment

Early atrophy of a speech-related brain area called temporal lobe and progressive degeneration of a cognitive one (frontal lobe) might be warning signs for Parkinson’s mild cognitive impairment later on, researchers report.

Their study, “Progressive brain atrophy in Parkinson’s disease patients who convert to mild cognitive impairment,” was published in CNS Neuroscience & Therapeutics.

Cognitive impairment is one of the most common non-motor complications of Parkinson’s and is associated with significant disability for patients, worsening their quality of life.

A substantial percentage of Parkinson’s patients will in time develop dementia; this appears to be preceded by mild cognitive impairment. Studies indicate mild cognitive impairment is associated with temporal and frontal cortex atrophy. “However, the consistency between these studies is poor,” the researchers noted.

It is known that the accumulation of harmful proteins and the short supply of the chemical messenger dopamine affect brain structure in Parkinson’s disease, but this exact relationship  remains to be understood, particularly the molecular and structural associations in patients who develop Parkinson’s-related mild cognitive impairment and those that don’t.

A Chinese team of researchers decided to investigate the changes in gray matter volume during cognitive degeneration by comparing Parkinson’s patients who developed mild cognitive impairment, those who did not and healthy subjects. Cognitive impairment has been linked to 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.

Ninety-four Parkinson’s patients without cognitive problems at the time of recruitment and 32 healthy subjects were included in this study. Participants underwent magnetic resonance imaging (MRI) and neuropsychological assessment at the study’s beginning and 28 months later.

Of the Parkinson’s sample, 24 subjects (16 men and eight women; mean age 63.1 years) developed disease-related mild cognitive impairment (converters) after 28 months of follow-up, while 70 individuals (43 men and 27 women; mean age 62.3 years) did not develop cognitive problems (non-converters).

Converters had significant right temporal atrophy at the beginning of the study and extensive temporal lobe degeneration 28 months later. Nonetheless, biochemical analysis showed no association between right temporal atrophy and Parkinson’s-related protein levels in cerebrospinal fluid. Sitting behind the ears, the temporal lobe is the region where sound is processed and where auditory language and speech comprehension systems are located.

Those who developed mild cognitive impairment also had progressive bilateral frontal lobe atrophy. Located directly behind the forehead, the frontal lobe carries out higher mental processes such as thinking, decision making, and planning.

Using DaT scan — an imaging technique that allows scientists to visualize the functioning of dopaminergic nerve cells — the team reported that loss of dopamine-producing neurons in the striatum (a brain region involved in motor control) of patients who progressed to mild cognitive impairment was correlated with right temporal atrophy.

The findings suggest that structural changes in the temporal and frontal lobes of Parkinson’s patients might be a biomarker for cognitive decline in the long term.

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Mild Cognitive Impairment in Parkinson’s Linked to Worse Memory, Attention Deficits, Study Reports

mild cognitive impairment

Parkinson’s disease patients with mild cognitive impairment (MCI) have a lower quality of life if their memory is impaired, according to a study that also revealed that MCI is associated with more severe attention and memory dysfunction in people with the disease.

The study, “Mild cognitive impairment in Parkinson’s disease: Characterization and impact on quality of life according to subtype,” appeared in the journal Geriatrics & Gerontology International.

MCI is a major risk factor for dementia and is more prevalent in Parkinson’s patients than in the general population. The prognosis of MCI in Parkinson’s depends on its specific subtypes, which may affect at least five domains: language, memory, attention, visuospatial function, and executive function, the latter of which involves goal-directed actions and ability to adapt to new situations.

Early MCI in Parkinson’s is associated with older age, greater motor impairment, and depression. In addition, research has shown that older age, being male, and motor dysfunction all lead to a greater risk of developing dementia in this patient population. However, a more detailed understanding of MCI in Parkinson’s is needed to improve patient management.

To address this, Brazilian researchers characterized MCI as either amnestic or non-amnestic and assessed its impact on quality of life. For reference, amnestic MCI impairs memory, while non-amnestic MCI affects other domains, namely language, attention, visuospatial skills, and/or executive function.

All participants underwent a neurological examination and were also evaluated using four clinical scales: Modified Hoehn and Yahr scale (which assesses the progression of Parkinson’s symptoms), Unified Parkinson’s Disease Rating Scale (UPDRS), Parkinson’s Disease Quality of Life Scale (PDQ-39), and the Schwab-England Activities of Daily Living Scale.

The study included 149 participants — 60 Parkinson’s patients and 81 individuals used as controls — of whom 52 patients (86%) and 60 controls (74%) had MCI. Overall, patients and controls did not differ in assessments of depression and global cognition, as evaluated with the Mini-Mental State Examination.

Amnestic MCI was diagnosed in 29 patients (mean age 62.1 years, 58.6% men) and 35 controls (61.3 years, 54.3% women), while non-amnestic MCI was found in 23 patients (62.1 years, 58.6% men) and 25 controls (61.3 years, 76% women).

Amnestic and non-amnestic Parkinson’s patients showed no differences in Parkinson’s duration and severity. However, amnestic patients revealed greater impairment in activities of daily living, meaning a lower quality of life.

Impairment in multiple domains was more common than in a single domain in both patients and controls. Regarding the predominant motor sign in Parkinson’s patients, the pure akinetic-rigid form — slow movements and rigidity — was more frequent in non-amnestic (69.65%) than in amnestic (37.9%) patients, but this was not statistically significant.

Neuropsychological evaluations showed that the most useful tests to assess cognition and differentiate amnestic from non-amnestic MCI were the Figure Memory Test, which addresses visual perception, language, attention, recognition, as well as visual short-term, long-term and learning memory; the Rey Auditory Verbal Learning Test; and the Trail Making Test, which analyzes visual attention and task switching.

Parkinson’s patients had worse scores in all three tests than controls. While episodic memory and verbal memory/learning were more significantly impaired in non-amnestic and amnestic patients than in controls, the dysfunction in attention was more pronounced in amnestic Parkinson’s patients.

These findings also revealed that attention was the most significantly impaired domain in both patients and controls, followed by memory.

“These results reveal that the [Parkinson’s] group had worse cognitive performance,” the researchers wrote. A longitudinal analysis of these participants will enable them to determine whether Parkinson’s patients are at a higher risk for dementia and whether this risk is different between amnestic an non-amnestic patients.

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Motor Dysfunction Among Predictive Markers of Parkinson’s in People with Sleep Disorder, Study Reports

sleep disorder, Parkinson's risk

Mild cognitive impairment, motor and olfactory deficits, and erectile dysfunction are among the markers able to predict the development of Parkinson’s and associated disorders in people with rapid eye movement sleep behavior disorder, according to a large study.

The research was published in the article, “Risk and predictors of dementia and parkinsonism in idiopathic REM sleep behaviour disorder: a multicentre study,” in the journal Brain.

Disorders characterized by the aggregation of alpha-synuclein — such as Parkinson’s, dementia with Lewy bodies, and multiple system atrophy  — may all have an early period of more than 10 years that’s characterized by signs of neurodegeneration, but without full clinical disease.

Unlike most markers of this early — or prodromal — period, rapid eye movement sleep behavior disorder (RBD) has been specifically linked to the development of synuclein-related diseases. RBD of no known cause, or idiopathic RBD (iRBD), occurs in approximately 1% of people older than 60, and usually converts to Parkinson’s or related disorders over a decade or more. This means that 1% of the elderly population have an identifiable but often undetected early-stage neurodegenerative syndrome.

As most studies on predictors of these parkinsonism diseases had been single-center, a team at The Neuro — Montreal Neurological Institute and Hospital — and the Montreal General Hospital of the McGill University Health Centre combined the research experience of 24 centers in North America, Europe, Seoul, and Sydney, which participated in the International RBD Study Group, to measure the risk of developing such disorders and test 21 potential predictors.

At the beginning of the study, a total of 1,280 participants (average age of 66.3 years, and 82.5% men) with iRBD but without parkinsonism or dementia underwent a variety of tests to assess sleep disturbances, motor function, cognition, depression, anxiety, olfaction, and autonomic function. The patients were then followed for up to 19 years. According to the team, this was “the largest study ever performed in iRBD.”

Over a mean period of 4.6 years, 352 patients (28%, with a mean age of 67.6 years) acquired an overt neurodegenerative syndrome, which corresponded to an annual rate of 6.25%. The risk of developing such diseases progressively increased from 10.6% after two years to 73.5% after 12 years. Among these 352 patients, 199 first showed signs of parkinsonism, while 153 developed dementia first.

Then the analysis revealed that motor dysfunction — as assessed through different measures — olfactory deficit, mild cognitive impairment, erectile dysfunction, an abnormal dopamine transporter (DAT) scan, color vision impairment, constipation, REM sleep without muscle atonia (reduced strength), and older age significantly predicted neurodegenerative disease development.

DAT is responsible for the uptake of dopamine — the neurotransmitter found in lower levels in people with Parkinson’s — into nerve cells.

In contrast, sex, insomnia, daytime sleepiness, restless legs syndrome, sleep apnea, urinary dysfunction, and depression or anxiety were not significant predictors.

Only those predictive markers that tested cognition and quantitative motor function differentiated the people who first developed dementia from those first showing signs of parkinsonism. These assessments of quantitative motor function were simple office-based tests that took less than five minutes.

“Clearly these are strong candidates for selecting patients for future neuroprotective trials, and could even obviate the need for sophisticated imaging techniques,” the investigators wrote.

“We confirmed a very high risk of (Parkinson’s) in people with REM sleep disorder and found several strong predictors of this progression,” Ron Postuma, the study’s lead author, said in a press release. “As new disease-modifying treatments are being developed for (Parkinson’s) and related diseases, these patients are ideal candidates for neuroprotective trials.”

A separate analysis estimated that 366 patients per experimental group would need to be recruited into a two-year trial for a therapy to reduce in half the incidence of RBD converting to parkinsonism or dementia. Increasing the trial duration or assuming a greater reduction in disease development led to lower estimates for the number of patients required. Also, this analysis showed that using different predictive markers to classify patients would significantly alter the number of patients required for clinical trials.

“Of course, exact sample size calculations will depend on the specifics of a clinical trial; nevertheless, the fact that 24 centers combined to produce these estimates can provide some confidence for trial planners that sample sizes will be representative of the global experience,” the study stated. “Notably, the total sample size for a future neuroprotective trial is less than the number of participants who were recruited to this study.”

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Cognitive Impairment Tests to Assess Dementia Risk Can Be Easier, Study Shows

cognitive impairment test

A shorter, simpler version of testing to diagnose mild cognitive impairment in Parkinson’s disease is just as effective as a lengthier evaluation at predicting the risk of developing Parkinson’s disease dementia, a report shows.

The study, “Risk of Parkinson’s Disease Dementia Related to Level I MDS PD-MCI,” was published in Movement Disorders.

Both cognitive decline and dementia are recognized as non-motor complications of Parkinson’s with significant clinical impact. Evidence suggests that mild cognitive impairment is a risk factor for Parkinson’s disease dementia (PDD).

The International Parkinson and Movement Disorder Society (MDS) has formulated two levels of criteria for diagnosing Parkinson’s-related mild cognitive impairment. Levels 1 and 2 differ in their methods of assessment, level of diagnostic certainty, and extent of clinical characterization.

Level 1 is comprised of a simpler, shorter series of cognitive tests, while level 2 entails a more extensive neuropsychological evaluation.

One study has shown that using level 2 criteria to assess mild cognitive impairment — which considered age, sex, years of education, depression and the severity of motor symptoms — can be effective at confirming an increased risk of patients developing dementia.

The University of Amsterdam researchers evaluated the prognostic value of testing mild cognitive impairment, using level 1 criteria as indicators of PDD.

“Comprehensive neuropsychological testing is not always possible because of time, cost, or patients’ inability to cooperate with a long assessment,” they said.

Looking at eight international studies, totaling 1,045 patients, they analyzed demographic and clinical data including age, sex, years of education, disease duration and neuropsychological examinations, based on the Unified Parkinson’s Disease Rating Scale (UPDRS) part III (motor tests), the Movement Disorder Society (MDS)-UPDRS III score, the Hoehn and Yahr scale (used to measure symptom progression), and an indicator of patient depression.

Level 1 criteria were applied, with one test of each of the five cognitive domains: attention, executive function— the ability to manage and organize thoughts, actions, and feelings — memory, visuospatial function, and language.

Survival analysis evaluated how each factor contributed to the risk of PDD.

In an initial evaluation17% of the patients were diagnosed with mild cognitive impairment. Median follow-up was 2.8 years and 151 out of the 1,045 (14.4%) patients developed dementia.

Only 9% of those without cognitive impairment at the beginning of the study developed dementia during follow-up, compared to 77% in the mild cognitive impairment group.

Worse performance in level 1 testing was associated with a higher risk of developing PDD dementia.

The evaluation also revealed that increasing age, male sex, and the severity of Parkinson’s motor symptoms independently heighten this risk.

Importantly, the study found that both levels of criteria had similar discriminant ability, meaning that the less extensive level 1 testing was effective at determining PDD risk.

Researchers also reported that level 1 criteria identified fewer mild cases, and associated them with relatively higher risk ratios, which they said could be attributed to the rating system used.  Level 1 criteria measures greater cognitive decline, when using the same cutoff as level 2 criteria.  For example, in level 1, at least two out of five tests need to show impairment, compared to at least two out of 10 tests in level 2.

“In conclusion, level I PD-MCI [mild cognitive impairment] criteria classification, based on a brief neuropsychological assessment, confers an independent contribution to the hazard of PDD while taking age, sex, education, PD motor sign severity, and depression into account. This finding supports the role of level I PD-MCI as a risk factor for PDD,” they wrote.

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Subjective Cognitive Decline Could Help Predict Parkinson’s Dementia, Study Contends

cognitive decline

Subjective cognitive decline in Parkinson’s disease could predict the development of dementia. As such, a suitable cognitive screening test could help provide an accurate diagnosis and prognosis.

The study with those findings, “Subjective cognitive decline and progression to dementia in Parkinson’s disease: a long-term follow-up study,” was published in Journal of Neurology.

Even during the early stages of disease, mild cognitive impairment can affect non-demented Parkinson’s patients, and is considered a risk factor for the development of dementia (PDD).

In fact, the prevalence of PDD increases as the disease progresses: from 28% after five years of evolution to 80% after 20 years of the disease.

Subjective cognitive decline — self-reported acquired difficulties with cognitive functioning — is common in the elderly and can be used as a predictor of dementia. In Alzheimer’s disease, subjective cognitive decline has been linked to disease-related tissue/molecular changes and a higher risk for dementia development. However, the predictive value of this type of cognitive status impairment has not been demonstrated yet in Parkinson’s disease.

Scientists from the University of La Laguna, Spain, investigated the neuropsychological profile of subjective cognitive decline in Parkinson’s disease and explored which components could better predict the development of PDD. The team also compared different screening tests to assess subjective cognitive complaints.

A total of 43 Parkinson’s patients and 20 healthy subjects were subjected to neuropsychological examination using a battery of cognitive tests. All patients were being medicated for Parkinson’s and were evaluated during their “on” state — when they are responding to medication and have reduced symptoms.

Subjective cognitive decline was diagnosed using two distinct approaches. A semi-structured interview in which the patient provided his/her subjective opinion on his/her attention, memory, spoken language, naming, written language, visuospatial skills and executive functions; diagnosis was considered when the patient had at least one cognitive complaint. Additionally, a subjective cognitive decline diagnosis also was established on the basis of the interview question concerning memory complaint.

For a mild cognitive impairment diagnosis, investigators followed the criteria proposed by the Movement Disorder Society (MDS)

Based on the results of the interview and on the MDS Task Force criteria, patients were diagnosed as having either subjective cognitive decline or mild cognitive impairment. Of the 43 patients, 13 (30.2%) were diagnosed with subjective cognitive decline, 22 (51.2%) with mild cognitive impairment and 8 (18.6%) had no subjective cognitive complaints. Difficulties in naming and memory were the most frequent cognitive complaints.

Based on memory complaints alone 10 patients (23.25%) were diagnosed with subjective cognitive decline. Interestingly, 10 of the 22 (45.45%) who had been diagnosed with mild cognitive impairment reported no memory complaints.

Mild cognitive impairment subjects performed poorer in the processing speed (the time it takes a person to do a mental task), executive functions (a set of mental skills that helps with organization and regulation), visuospatial skills, memory, and language domains, compared to the other groups.

There were no significant differences between healthy participants (controls)  and Parkinson’s disease patients with subjective cognitive decline in any of the neuropsychological measures.

The team also assessed how many patients diagnosed with subjective cognitive decline progressed to dementia after a mean follow-up of 7.5 years. Fifty percent of mild cognitive impairment patients, 33.3% of individuals diagnosed with subjective cognitive decline, and 14.3% of patients without subjective cognitive complaints developed dementia, which was found to be associated with a poor performance in verbal and visuospatial memory and naming at the beginning of the study.

Additionally, both the language and memory domains were good predictors of dementia development.

“These results are highly relevant for future investigations and also for clinicians: the [subjective cognitive decline] assessment is frequently the first step of cognitive examination and can influence future decisions (e.g., to administer a screening test or a comprehensive neuropsychological assessment),” researchers wrote.

“Assessments that do not include procedures to adequately explore cognitive complaints may underestimate the proportion of [Parkinson’s-related subjective cognitive decline] and, therefore, [mild cognitive impairment] and thus misclassify patients as [Parkinson’s disease] with normal cognition, especially when brief cognitive examinations are chosen,” they concluded.

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Parkinson’s Patients Without Cognitive Impairment Have Normal Life Expectancy, Study Suggests

life expectancy, Parkinson's

While patients with some types of parkinsonism have a shorter lifespan, those with Parkinson’s disease without cognitive impairment have a normal life expectancy, a Swedish population-based study suggests.

The study, “Early predictors of mortality in parkinsonism and Parkinson disease: A population-based study,” was published in the journal Neurology.

Studies have shown that life expectancy for Parkinson’s patients is reduced. However, conflicting data exists regarding the size of, and specific factors accounting for, the reduced survival compared with the general population.

Most studies of survival in Parkinson’s disease have been “hospital-based or have used register-based case-finding methods,” the researchers wrote. However, these designs may give rise to biased results.

In particular, cases of mild Parkinson’s disease may have been underrepresented, along with a lack of referral of older patients to hospital clinics.

“There are also few studies of the survival in unselected populations of patients with new-onset idiopathic parkinsonism (including atypical parkinsonism), rather than PD [Parkinson’s disease],” the researchers said.

Parkinsonism is a general term for neurological disorders that cause movement problems similar to those of Parkinson’s disease.

Parkinson’s dementia has also been associated with shorter survival, but mild cognitive impairment — an intermediate clinical stage not meeting the criteria for dementia — has not been studied in detail.

Aiming to address these gaps, the researchers assessed all-cause mortality and associated risk factors in a group of 182 Swedish patients with idiopathic parkinsonism, including 143 with Parkinson’s, 13 with multiple system atrophy (MSA), and 18 with progressive supranuclear palsy (PSP).

Patients were diagnosed from January 2004 through April 2009 in an area with 142,000 inhabitants. All underwent neurological, neuropsychological, neuroimaging, and laboratory tests, and received standard or advanced treatments during a long-term follow-up of up to 13.5 years. Memory and thinking skills, along with Parkinson’s symptoms, were assessed at the start of the study and at least once a year.

The team used a battery of validated tests, including the Unified Parkinson’s Disease Rating Scale (UPDRS) to assess both motor and non-motor symptoms; the modified Hoehn and Yahr Scale for disease progression; Mini-Mental State Examination (MMSE), which measures cognitive impairment; and the 39-item Parkinson’s Disease Questionnaire, a self-administered questionnaire that addresses aspects of functioning and well-being.

Assuming a mean age of 71.7 years at baseline (the beginning of study) in idiopathic parkinsonism — meaning the disease is of unknown causes — the expected survival was 9.6 years for people with Parkinson’s and 6.1 years for people with PSP or MSA (atypical parkinsonism).

A total of 109 patients died during the study, including 54% of those with Parkinson’s, 89% of people with PSP, and 92% of patients with MSA. Of note, the lower survival observed in people with MSA or PSP — who had a mortality rate more than three times higher than the general population — was in line with previous studies.

In early Parkinson’s disease, mild cognitive impairment, freezing of gait, hyposmia (reduced sense of smell), decreased dopamine transporter activity in brain areas called caudate and putamen (implicated in motor control), and elevated white blood cells in the cerebrospinal fluid — the liquid surrounding the brain and spinal cord — (suggesting an activated immune response) were significantly associated with shorter survival.

Of note, the dopamine transporter is a protein responsible for the uptake of dopamine — a neurotransmitter present in low levels in Parkinson’s patients — back into neurons.

Importantly, the expected survival in Parkinson’s disease was 11.6 years without mild cognitive impairment and 8.2 years with mild cognitive impairment.

“Patients with Parkinson disease presenting with normal cognitive function seem to have a largely normal life expectancy,” the researchers wrote.

“The findings underscore the importance of an early [Parkinson’s]-MCI diagnosis,” they said.

“This is good news for many people with Parkinson’s and their families,” David Bäckström, MD, the study’s first author from Umeå University in Sweden said in a press release.

Among the study’s limitations, the investigators mentioned that autopsies to confirm diagnosis were only conducted in five of the 109 people who died, and none of those with MSA. However, they believe that the long duration of follow-up minimized the risk of an incorrect diagnosis.

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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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Better Biomarkers Needed to Diagnose, Predict Risk of Mild Cognitive Impairment

Parkinson's mild cognitive impairment

There still are no reliable biomarkers for early detection, or to characterize and predict risk of dementia, in Parkinson’s disease, according to a recent analysis.

Several studies on the cognitive deficits, progression to dementia, potential biomarkers and the mechanisms underlying Parkinson’s disease mild cognitive impairment (PD-MCI) were analyzed by University College London researchers in the review study “Mild Cognitive Impairment in Parkinson’s Disease—What Is It?,” which was published in the journal Current Neurology and Neuroscience Reports.

Large-scale studies have shown that PD-MCI is not only important, but also common, even at the earliest stages of Parkinson’s disease. In fact, MCI signs can be detected before the onset of Parkinson’s motor symptoms.

About half of Parkinson’s patients with cognitive impairment will progress to dementia in the first 10 years after diagnosis. But considerable variation exists among this patient population regarding the type of cognitive domains affected, the timing, severity and risk of progression to dementia.

Accordingly, PD-MCI is emerging as an intermediate stage between normal cognition and dementia, similarly to the stage of amnestic mild cognitive impairment in Alzheimer’s disease.

Epidemiological studies report that 25 to 50 percent of Parkinson’s patients have MCI, depending on the population and the clinical setting. Identifying individuals with early signs of PD-MCI or at risk of dementia is important to provide early interventions, estimate prognosis, and discover therapeutic targets.

In an effort to clarify the diagnosis of PD-MCI, a task force from the International Parkinson and Movement Disorder Society (MDS) provided a unified definition. According to the new criteria, PD-MCI is defined as an “insidious decline in cognitive abilities reported by patient or informant or observed by the clinician, not caused by other comorbidities.”

Unlike dementia, MCI deficits are detectable, but do not interfere with patients’ autonomy.

The nature and severity of PD-MCI is quite variable. The dominant manifestation does not involve memory. But there are other subtypes with deficits in attention, memory, executive function, psychomotor speed and visuospatial abilities. In some people the deficits can involve multiple cognitive domains.

The MDS has recommended a battery of tests to assess involvement of single or multiple domains and report exactly which domains are affected.

In general, patients with PD-MCI are at higher risk of progressing to dementia than Parkinson patients without MCI. Importantly, studies report that 11 to 28 percent of patients with PD-MCI revert to normal cognition during follow-up.

The variability of these results is likely to reflect differences in study populations, assessment methods and definitions.

Some factors can increase risk of cognitive deficits in Parkinson’s, including being older than 70, akinetic rigid phenotype (freezing and/or falls), poor verbal fluency and higher rates of comorbidities. Higher rates of progression to dementia are associated with older age, depression and a non-tremor clinical manifestations.

Exploring biomarkers

Biomarkers such as amyloid beta protein in the cerebrospinal fluid, and magnetic resonance imaging of the brain, may become important for providing insights into mechanisms of cognitive involvement and for accessing disease progression.

The mechanisms underlying PD-MCI likely involve a combination of factors. Brain aggregates of the proteins alpha synuclein, beta amyloid and tau — the latter two also characteristic of Alzheimer’s disease —  are likely to play a role.

Besides, some studies suggest that changes in specific neurotransmitters — chemical messengers used to communicate between neurons, including acetylcholine, noradrenaline and dopamine — also contribute to cognitive impairment.

Some questions regarding PD-MCI remain unresolved. One of them is the distinction between dementia with Lewy bodies (intracellular accumulations of alpha synuclein) and Parkinson’s dementia.

Dementia with Lewy bodies emerges early, before or within the first year of Parkinsonism, while Parkinson’s dementia is defined as a progressive decline appearing at least one year after motor symptoms are noticeable.

However, given the reports of people with cognitive deficits even before characteristic manifestations of Parkinson’s, perhaps cognitive impairments are the first signs of Parkinson’s disease and may start earlier than believed.

Some studies report that some PD-MCI sub-groups, particularly those with deficits in visuospatial performance, are at the highest risk of dementia.

This underscores the need for better assessment methods and biomarkers of PD-MCI to allow well-defined characterizations of the cognitive deficits and predict who is more prone to dementia.

Although the antipsychotics Nuplazid (pimavanserin) and Clozaril (clozapine) are the only therapies shown to improve Parkinson’s disease psychosis (PDP) symptoms without impairing motor function, there currently are no pharmacological treatments specifically for PD-MCI.

The effect of current experimental therapies on cognition is unknown. Some studies suggest that cognitive training can improve overall cognition in Parkinson’s patients, although the effect seems small.

Physical exercise shows more promising results. Several studies report that moderate intensity aerobic exercises performed two to three times a week lead to some improvement in executive and language functions.

However, Acadia Pharmaceuticals, Nuplazid’s manufacturer, is planning to conduct additional studies of the therapy in PD psychosis patients with a broader range of cognitive abilities and formal cognitive diagnoses, including mild cognitive impairment and dementia.

“Maintaining wide definitions, with poorly differentiated cognitive profiles, prevents accurate comparisons across studies,” researchers wrote. “There is clearly a need for better cognitive phenotyping to enable well-defined sub-groups that are more likely to show similar rates of disease progression.”

“Recognizing the earliest stages of cognitive involvement will allow disease stratification and personalized treatment, with the potential for early intervention. It will enable better-powered clinical trials, and potential outcome measures, ultimately to develop treatments to prevent the progression of dementia in PD,” the review concluded.

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Source: Parkinson's News Today