Cognitive impairment in Parkinson’s disease: a report from a multidisciplinary symposium on unmet needs and future directions to maintain cognitive health
Cognitive impairment in Parkinson's disease: a report from a multidisciplinary symposium on unmet needs and future directions to maintain cognitive health
Jennifer G. Goldman 9
Beth A. Vernaleo 10
Richard Camicioli 11
Nabila Dahodwala 12
Roseanne D. Dobkin 13
Terry Ellis 14
James E. Galvin 15
Connie Marras 16
Jerri Edwards 17
Julie Fields 19
Robyn Golden 0
Jason Karlawish 1
Bonnie Levin 2
Lisa Shulman 3
Glenn Smith 4
Christine Tangney 5
Cathi A. Thomas 6
Alexander I. Tr?ster 7
Ergun Y. Uc 8
Noreen Coyan 18
Crystal Ellman 18
Mike Ellman 18
Charlie Hoffman 20
Susan Hoffman 20
Don Simmonds 18
0 Department of Health and Aging, Rush University Medical Center , Chicago, IL , USA
1 Department of Medicine, University of Pennsylvania , Philadelphia, PA , USA
2 Department of Neurology, Division of Neuropsychology, University of Miami , Miami, FL , USA
3 Department of Neurology, University of Maryland School of Medicine , Baltimore, MD , USA
4 Department of Clinical and Health Psychology, University of Florida , Gainesville, FL , USA
5 Department of Clinical Nutrition, College of Health Sciences, Rush University Medical Center , Chicago, IL , USA
6 Department of Neurology, Boston University Medical Campus , Boston, MA , USA
7 Department of Clinical Neuropsychology and Center for Neuromodulation, Barrow Neurological Institute , Phoenix, AZ , USA
8 Department of Neurology, University of Iowa, and Neurology Service , Iowa City , Veterans Affairs Health Care Systen , Iowa City, IA , USA
9 Department of Neurological Sciences, Section of Parkinson Disease and Movement Disorders, Rush University Medical Center , Chicago, IL , USA
10 Parkinson's Foundation , New York, NY , USA
11 Department of Medicine, University of Alberta , Edmonton, AB , Canada
12 Department of Neurology, University of Pennsylvania , Philadelphia, PA , USA
13 Department of Psychiatry, Rutgers The State University of New Jersey , New Brunswick, NJ , USA
14 Department of Physical Therapy and Athletic Training and Center for Neurorehabilitation, Boston University , Boston, MA , USA
15 Charles E. Schmidt College of Medicine, Florida Atlantic University , Boca Raton, FL , USA
16 Morton and Gloria Shulman Movement Disorders Centre and the Edmond J. Safra Program in Parkinson's disease, Toronto Western Hospital, University Health Network, University of Toronto , Toronto, ON , Canada
17 University of South Florida , Tampa, FL , USA
18 Illinois USA , USA
19 Department of Psychiatry and Psychology, Mayo Clinic , Rochester, MN , USA
20 Colorado , USA
REVIEW ARTICLE People with Parkinson's disease (PD) and their care partners frequently report cognitive decline as one of their greatest concerns. Mild cognitive impairment affects approximately 20-50% of people with PD, and longitudinal studies reveal dementia in up to 80% of PD. Through the Parkinson's Disease Foundation Community Choice Research Award Program, the PD community identified maintaining cognitive function as one of their major unmet needs. In response, a working group of experts across multiple disciplines was organized to evaluate the unmet needs, current challenges, and future opportunities related to cognitive impairment in PD. Specific conference goals included defining the current state in the field and gaps regarding cognitive issues in PD from patient, care partner, and healthcare professional viewpoints; discussing non-pharmacological interventions to help maintain cognitive function; forming recommendations for what people with PD can do at all disease stages to maintain cognitive health; and proposing ideas for how healthcare professionals can approach cognitive changes in PD. This paper summarizes the discussions of the conference, first by addressing what is currently known about cognitive dysfunction in PD and discussing several non-pharmacological interventions that are often suggested to people with PD. Second, based on the conference discussions, we provide considerations for people with PD for maintaining cognitive health and for healthcare professionals and care partners when working with people with PD experiencing cognitive impairment. Furthermore, we highlight key issues and knowledge gaps that need to be addressed in order to advance research in cognition in PD and improve clinical care.
Perspectives on cognitive impairment from people with
Parkinson?s disease and care partners in the working group
Quotes from people with PD:
?Sometimes my brain ?freezes up,? kind of like my legs
sometimes do. Finding the words I want to say is very hard, and
my thoughts seem like they are blank.?
?I wish that the doctor had told me that cognitive changes
could be one of the results of the disease. My clinic visits have
focused much more on physical signs and symptoms. The few
times cognition has been addressed, the comments were very
Quotes from PD care partners:
?The most bothersome is attention, which we call ?chasing
rabbits? at our house. Early on this manifested as flitting from task
to task without completion. However, cognitive symptoms have
started to affect communication, which in turn affects our
relationship. My husband?s frustration in turn sparks irritation in
both of us. I sometimes wonder if the same is not occurring with
friends, and they are too polite to tell me.?
?My husband has lost his initiative in social situations. He listens
but rarely contributes and may get confused in the conversation. I
miss the social interactions that we used to have with friends with
little planning. With just a suggestion, it used to happen.?
Along with people with PD and their care partners, a
multidisciplinary group of experts convened for a conference
workshop entitled, ?Non-pharmaceutical ways to maintain
1 What is one recommendation you would give to someone newly diagnosed or early-stage PD:
2. What is one recommendation you would give to someone in mid-stage PD:
3. What is one recommendation you would give to someone with PD as they prepare for cognitive decline associated with advanced PD?
4. What is one recommendation you would give to a care partner regarding how to cope with cognitive changes in their loved one:
5. What is one recommendation you would give to a care partner who is taking care of a loved one with advanced PD and experiencing cognitive
6. What do you think healthcare professionals should recommend to patients newly diagnosed or early-stage PD:
To maintain cognitive health?
Regarding cognitive changes they may experience?
To maintain cognitive health?
Regarding cognitive changes they may experience?
7. What do you think healthcare professionals should recommend to patients in mid-stage PD:
8. What do you think healthcare professionals should tell patients in preparation for cognitive decline associated with advanced PD?
9. What recommendation would you give to academic researchers who may be working with PD patients experiencing cognitive decline?
10. Is there anything else you would want to recommend to either PD patients, care partners, or healthcare professionals? Please tell us here
cognitive function in PD.? This workshop stemmed from the 2016
Parkinson?s Disease Foundation Community Choice Research
Award Program, in which cognitive function in PD was selected
as a community priority. In response, a program on this topic was
designed, bringing together clinicians and researchers with a wide
range of expertise as well as people directly affected by PD. In
attendance were 19 clinicians and researchers including: five
movement disorder neurologists, one cognitive neurologist, two
psychologists, four neuropsychologists, one physical therapist, one
nutritionist, one registered nurse, one social worker, one geriatric
neurologist, one gerontologist/clinical ethicist, and one researcher
from the Parkinson?s Foundation. Also in attendance were three
people with PD (one female, two male) and their care partner
spouses (one male, two female). The conference covered nine
topics, which were selected ahead of time by the conference
leaders (J.G.G., B.A.V.): 1. defining cognitive issues in PD, 2. features
and etiology of PD cognitive impairment, 3. cognitive aging, 4.
clinical measures of cognition, 5. physical exercise, 6. cognitive
exercise, 7. nutrition, 8. caregiver involvement in PD cognitive
issues, and 9. decision-making capacity. Each topic was discussed
with respect to its current state in the field, perceived unmet
needs, and potential future directions, as based on literature
review, expert opinion, and conference group discussion.
Participants then generated questions and provided feedback after the
conference, from which proposed recommendations were
developed to help people with PD be proactive about their cognitive
health. These questions aimed to elicit recommendations
from healthcare professionals working with PD patients
across disease stages (Table 1) as well as responses from PD
community members regarding what they wished the doctor had
told them about cognitive changes at different stages of their PD
In this review, we first provide an overview addressing what is
currently known about cognitive dysfunction in PD, describing
unmet needs and gaps, and highlighting future directions for each
topic covered. Second, based on the conference discussions, we
present the working group?s proposed recommendations for
people with PD and their care partners when experiencing
cognitive issues and for healthcare professionals when working
with people with PD facing cognitive challenges.
CURRENT STATE OF KNOWLEDGE ON COGNITIVE IMPAIRMENT IN PD
Characteristics, etiologies, and risk factors
Cognitive impairment in PD is heterogeneous in its severity, rate
of progression, and affected cognitive domains.1 It varies from
subtle cognitive changes or deficits, to mild cognitive impairment
(MCI) in which cognitive deficits occur but do not significantly
disrupt daily living, to dementia (PDD) in which a greater degree
and variety of cognitive deficits substantially affect daily
functioning. MCI in PD increases the risk of conversion to
dementia.2,3 Additional evidence, however, suggests that PD-MCI
may not always progress to dementia; on longitudinal
assessments, some remain stable as ?MCI? and others revert to normal
cognition.2,4,5 Thus, progression to dementia is not inevitable but
develops in about 80% of patients with PD durations, especially
longer than 20 years.6 Risk factors for PDD include advanced age,
older age of disease onset, limited cognitive reserve,
hallucinations, and predominant gait dysfunction.6,7 Cognitive deficits in
PD typically affect executive functions, attention, visuospatial
function, and processing speed.8 The pattern of cognitive
impairment varies, however, in not only the extent to which
different cognitive domains are affected but also which domains
are affected first. Some people with PD cognitive impairment may
have greater memory deficits than non-amnestic dysfunction.9
The heterogeneity in presentation and evolution of PD cognitive
impairment is not fully understood but may reflect, in part,
influences of co-morbid pathologies such as Alzheimer?s disease
(AD) or cerebrovascular disease as well as genetics, environment,
and cognitive reserve, among others.10 The CamPaIGN study
provides evidence for the heterogeneity of PD cognitive subtypes
and different rates of progression, suggesting a ?dual hypothesis?;
two distinct cognitive subtypes emerged in this longitudinal study
) a frontostriatal/executive function profile associated with
dopamine depletion interacting with the COMT genotype and not
necessarily progressing to dementia and (
) a posterior cortical
1. In your first year of having PD, what is one thing you wish your doctor told you about:
Cognitive changes you or your loved one may experience?
Coping with cognitive changes you or your loved one may have?
Cognitive changes you or your loved one may experience?
Coping with cognitive changes you or your loved one may have?
2. After having PD for several years, what is one thing you wish your doctor told you about:
3. What is one thing you wish you doctor would tell you in preparation for cognitive changes in yourself or your loved one associated with advanced
4. Is there anything else you would want to know about cognitive changes, or how to cope with cognitive changes? Please tell us here
dysfunction profile with deficits in impaired language/semantic
fluency and visuospatial orientation/pentagon copying, associated
with AD pathology, non-dopaminergic transmitters, and
apolipoprotein epsilon 4 (ApoE4) genotype.11,12
Neuropathological studies of patients who died with PDD
demonstrate widespread cortical and limbic involvement with
neurodegeneration, neuronal loss, and deposition of Lewy bodies
and Lewy neurites.13 Clinical correlations, however, yield
conflicting results as to which neuroanatomical areas and
neuropathologies are most important in the clinical expression of PD cognitive
impairment.13 Basal ganglia pathology, particularly in its
associative (cognitive) areas, may also contribute to cognitive deficits.14
While PD is an ?-synuclein-mediated disease, autopsy studies and
cerebrospinal fluid biomarker studies suggest that amyloid
pathology contributes to cognitive impairment in PD in some
cases.15,16 Co-existing synuclein and amyloid pathology may
invoke synergistic processes.17,18 Cerebrovascular disease
contributes to some cases of PD cognitive impairment, with evidence
of microvascular ischemia on pathology and white matter
hyperintensities on neuroimaging.13,19 PD cognitive impairment
also reflects dopaminergic, cholinergic, serotonergic, and
noradrenergic neurotransmitter deficiencies. Functional neuroimaging
and neuropathological studies measuring neurotransmitters
support the roles of dopaminergic and cholinergic deficits in PD
The prevalence of dementia in PD increases with age, disease
duration, motor severity, postural instability/gait disorder
phenotype, baseline cognitive impairment, and presence of other
nonmotor and neuropsychiatric issues.7,21 REM sleep behavior
disorder is closely related to PD cognitive impairment,22,23 and
greater daytime sleepiness has been associated with worse
cognition in PD.24,25 Social isolation, depression, and medical
illness may worsen cognition in general and in PD. Even after
accounting for these factors, however, cognitive function varies
among individuals. This variable expression implies potential
genetic or environmental modifiers. Some genetic causes or risk
factors for PD (e.g., LRRK2) are generally not associated with
prominent cognitive dysfunction, whereas ?-synuclein duplication
and triplications, GBA, and MAPT mutations have been linked to
cognitive deficits and dementia.26?29 The ApoE4 allele has been
associated with memory and semantic fluency in PD26,27 and may
increase the risk of PDD, though studies are conflicting.30,31 Study
results have been conflicting regarding the role of polymorphisms
in BDNF and COMT genes in PD cognitive impairment.11,27,32,33 In
non-PD populations, co-morbidities such as obesity, diabetes, and
hypertension may be associated with cognitive decline.34,35 This is
also the case for diets high in saturated fat, trans-fat, and refined
carbohydrates, or low in berries, green leafy vegetables, nuts,
vitamin B12, and folate.36 At present, data are limited regarding
the role of co-morbidities and diet in PD cognitive
impairment.37,38 Preliminary reports suggest that elevated levels
of homocysteine and plasma phospholipids and lower levels
of serum uric acid may be associated with worse cognition in
PD.39?41 Environmental risk factors present compelling
opportunities for intervention. However, whether modifying these risk
factors would change the progression of PD cognitive impairment
What is normal cognitive aging and how does PD fit in?
Many people attribute cognitive changes to ?aging,? and a major
concern expressed by people with PD and their care partners is
whether cognitive deficits are related to aging or to PD. Cognitive
changes in people with PD need to be benchmarked against
normative data and age-related changes. Cognitive decline
without dementia can occur in aging,42 perhaps because
neuropathological processes such as neuronal loss, deposition of
amyloid, tau, and ?-synuclein, and vascular changes, often found
post-mortem, are common as we age.43 The progression of
cognitive decline is a key element in attributing changes to
underlying disease-related processes. In general, cognitive
changes in ?normal? aging should not interfere significantly with
everyday activities that require cognitive abilities. If they do,
however, this may suggest an abnormal process and signal an
increased risk of developing MCI or dementia.44 Changes in
functional abilities and everyday activities due to cognitive decline
can be difficult to identify if they are mild. Distinguishing whether
problems in everyday activities are due to cognitive or motor
problems in PD, or a combination of both, can be challenging, and
appropriate measures for determining this are needed.
In ?normal? aging, cognitive problems typically involve difficulty
with recalling and generating words or names (tip of the tongue
phenomenon). Deficits in word or name recall, however, are also
common in PD.1,7 When objective evidence accompanies
subjective cognitive changes without a substantial impact on
function, this is defined as MCI,44 a concept also applied in PD.45
MCI is a risk factor for dementia in both aging44 and in PD
populations.44,46 Community-based studies demonstrate that
aging is associated with changes in several cognitive domains,
notably speeded measures and recall (aspects of the so-called
fluid intelligence), but with relative preservation of others such as
vocabulary (crystallized intelligence).47 Normative ranges for
cognitive performance have been defined for older adults and
throughout the life span.
Older people show greater variability on cognitive test
performance, particularly in speeded measures (e.g., reaction
time), and decline in measures of attention (e.g., divided attention
and working memory).48 Cognitive fluctuations, impaired
attention, slowing, and performance variability are hallmarks of Lewy
body disorders including PDD, where they are exaggerated
compared to changes of normal aging.49 Disentangling effects
of age-related and disease-related changes on cognition,
comorbid non-motor issues (e.g., sleep disturbances, mood
disorders, apathy, and fatigue), and medications or deep brain
stimulation treatments in PD cognitive impairment represent
several unmet needs.
CLINICAL MEASURES OF COGNITION IN PD
Determining objective changes in cognitive function frequently
involves neuropsychological testing. Test selection may depend
on a number of factors such as age, education, and language. Test
performance can be affected by motor function as well as
physiological changes of aging (e.g., vision loss, hearing loss,
sensory-motor changes). Therefore, neuropsychological testing in
PD should include some measures that do not rely on manual
dexterity or motor speed as these can be compromised and make
it difficult to separate motor symptomatology from a given
Cognitive function in PD is frequently assessed in clinical and
research settings and by physicians, neuropsychologists,
occupational therapists, or speech therapists. Evaluations may include
tests of global cognitive abilities or individual neuropsychological
tests capturing different cognitive domains, or a combination of
both.50 Clinical measures target the major cognitive domains:
orientation, attention, executive function, abstract reasoning,
memory, language, perception, visuospatial abilities, praxis, and
motor skills.51 Methods of cognitive evaluation depend on the
goals of the assessment, but formal neuropsychological testing
remains a gold standard. It is also important to assess mood (e.g.,
depression, anxiety, apathy), behavioral issues (e.g., psychosis),
sleep disturbances (e.g., excessive daytime sleepiness), and
functional abilities in PD as these can impact cognition as well
as quality of life. Eliciting cognitive complaints may come directly
from the patient, but gathering information from a reliable
informant is imperative. The presence of cognitive decline can be
gleaned from patient and informant reports, estimates based on
premorbid IQ, and serial neuropsychological evaluations.
Interpreting studies of cognitive function in PD requires an
understanding of not only what is ?normal? vs. ?pathological? aging and
how it is measured but also the context of PD-related motor and
non-motor features, effects of medical or surgical treatments, and
co-morbid neuropsychiatric complications.
Many tests of global cognition have been studied or reviewed
in PD, including the Mini-Mental State Examination, Montreal
Cognitive Assessment (MoCA), PD-Cognitive Rating Scale,
Addenbrooke?s Cognitive Examination, among others.45,50,52,53 Many
tests covering different cognitive domains (e.g., attention,
executive function, language, memory, or visuospatial functions) also
have been used in PD. The Movement Disorder Society (MDS) Task
Forces for PDD and PD-MCI diagnostic criteria provide
recommendations for assessments of cognitive domains and
neuropsychological tests.45,54 Standardized protocols and PD-specific
neuropsychological batteries may provide uniformity across
multiple centers and research trials.
Several other gaps remain in our ability to assess cognition in
PD. There is no standard way to elicit cognitive complaints, nor
any guidance on which questions are the most sensitive. Cognitive
screening tests are frequently not specific for PD cognitive deficits,
and their responsiveness to change over time or with intervention
is not fully known. The lack of consensus regarding PD cognitive
evaluation and defining impairment may contribute to the
heterogeneity and potentially false cognitive classifications of
people with PD. Normative data and sources vary, and there is
little normative data available for those with low education or
socioeconomic status. Furthermore, functional assessments lack
standardization, although there are several PD-specific tools
available including performance-based measures.55?58 Validation
of the MDS Task Force diagnostic criteria for PD-MCI is
underway,45,59 and PD-MCI is now being used in clinical trial inclusion
criteria. Despite increased recognition of cognitive impairment in
PD, cognition is not routinely or consistently assessed in the clinic,
in contrast to motor function. Baseline and serial cognitive
evaluations need to be considered in order to fully elucidate the
full spectrum of cognitive impairment in PD.
EVIDENCE FOR NON-PHARMACOLOGICAL INTERVENTIONS
FOR PD COGNITIVE IMPAIRMENT
Physical exercise programs: can they help cognition in PD?
Studies in healthy older adults suggest that physical exercise
improves cognitive function. A meta-analysis of 29 randomized
controlled trials including 2049 participants revealed statistically
significant, but clinically modest, improvements in attention,
processing speed, executive function, and memory following
6 weeks to 18 months of aerobic exercise (most often performed
three times weekly at 70% peak oxygen uptake for
2.5?4 months).60 In older adults at risk for cognitive decline,
significant improvements in global cognition occurred with at
least 150 min of moderate-intensity physical activity per week
over 6 months, with benefits persisting after 18 months.61
However, among sedentary older adults in the Lifestyle
Interventions and Independence for Elders (LIFE) study, a 24-month
moderate-intensity exercise program (aerobic, resistance,
flexibility exercises) compared to a health education program did not
improve global or domain-specific cognitive function. Participants
in the physical activity group who were 80 years or older or had
worse baseline physical performance, however, had greater
changes in executive function composite scores compared to
the health education group.62
Studies examining the effects of physical exercise on cognitive
function in PD are emerging, and results are promising.63?66
Aerobic exercise may improve executive function in PD,67
consistent with findings in studies of healthy older adults. In
one study, 49 people with mild to moderate PD completed
participation of 45 min of aerobic walking three times weekly over
6 months; there were significant improvements in exercisers in
executive function (Flanker task scores) along with improvements
in scores for motor severity, fatigue, depression, and quality of
life.68 In a randomized controlled trial (n = 28), people with PD
improved specifically in executive function measured by verbal
fluency and spatial working memory tasks following participation
in 60 min of progressive aerobic and anaerobic training twice
weekly over 3 months.69
Strengthening exercises also may benefit cognition in PD. In a
randomized controlled trial, 51 people with mild to moderate PD
participated in either a progressive resistance exercise program or
a non-progressive strengthening program twice weekly over 2
years. Participants in both groups improved in working memory
(Digit Span) and executive function (Stroop test) at 24 months,
whereas only the progressive resistance group had significantly
better attention.70 In a multi-modal exercise study (aerobic,
strengthening, flexibility, and balance exercises) involving 20
people with PD, significant improvements in executive function
(Wisconsin Card Sorting Test) occurred in the exercise group
compared to the control group.71 A community-based 12-week
tango program (90 min, twice weekly) in 24 people with mild to
moderate PD demonstrated improved spatial cognition compared
to those who participated in educational sessions (n = 9).72
Collectively, these results provide preliminary evidence for
benefits of different types of physical exercise on cognitive
function, particularly executive functions, in people with mild to
Several questions remain unanswered regarding effects of
physical exercise on PD cognitive impairment or decline. We need
to know more about the optimal type(s) of exercise (i.e., aerobic,
strengthening, or a combination), dose (e.g., frequency, intensity),
duration, and timing to improve cognitive function in PD. We
need a better understanding of the neurobiological and
physiological mechanisms of physical exercise (i.e., modulation of
dopamine transmission, neurotrophic factors, corticomotor
excitability, and structural, functional, and metabolic changes in the
brain, among others) that may account for cognitive
improvements observed. We need to understand if the impact of physical
exercise on cognition is global or selective for particular cognitive
domains (e.g., executive function, memory). These factors will
shape clinical trial design in the selection of target outcome
measures and optimal PD populations and disease stages. As
many studies to date have small sample sizes, did not include
control groups, and used various interventions and doses,
rigorously designed trials are needed. Cognition needs to be
measured as the primary outcome, which is not always the case in
previous studies of exercise and cognition in PD. An
understanding of the impact of physical exercise on cognitive function
during real-world activities is needed.
Cognitive interventions: can they help cognition in PD?
There are several different types of cognitive interventions.
Cognitive remediation or rehabilitation techniques include broad,
multi-component approaches typically aimed at recovering an
individual?s abilities in the face of loss (e.g., stroke or head injury).
Some approaches may be indirect (i.e., targeting a third variable
such as mood or social/activity engagement that may thereby
influence a cognitive process or strategy),73?75 and others involve
multifaceted therapeutic techniques such as combining cognitive
training, support groups, wellness education, and/or mental
health counseling.76 Cognitive training refers to specific ?brain
exercises? that involve targeted practice with the goal of
improving particular cognitive abilities (e.g., memory, speed of
processing, attention, executive function) and by using different
cognitive training techniques or strategies (e.g., paying attention
to, remembering, planning, or organizing information). Cognitive
training is based on the idea that cognitive functions can be
?strengthened? over time with practice, similar to physical exercise
strengthening muscles. Non-pharmacological approaches like
cognitive training are of great interest, due to their potential to
alleviate cognitive symptoms, provide individualized approaches,
and avoid medication side effects. However, there has been rising
public concern that many programs and products claim to stave
off cognitive decline and dementia. Commissioned experts
evaluated the science behind these interventions and noted that
cognitive training was one of the few interventions (along with
physical exercise and blood pressure control) to receive a positive
recommendation and ?encouraging? evidence from the National
Academies of Sciences, Engineering, and Medicine committee.77
Several studies examine the effects of cognitive interventions in
PD, but few provide conclusive evidence regarding benefits of
engaging in such activities.78 To date, no cognitive intervention
studies among persons with PD meet all of the criteria proposed
in the Institute of Medicine?s Report on Cognitive Aging for
evaluating cognitive training programs.79 These criteria include:
reliable transfer to other similarly constructed laboratory training
tasks, transferability to relevant real-world tasks, efficacy
established through comparisons of active control and experimental
groups with equivalent expectations for benefit, skill retention
post training, and replicability across studies. Nonetheless,
preliminary evidence holds promise. Data from the few
welldesigned randomized controlled trials of cognitive training in PD
conducted to date reveal large and statistically significant effect
sizes for cognitive domains known to be impaired in PD, such as
working memory, processing speed, and executive functioning
(i.e., also seemingly more frontostriatal-type deficits), but not
posterior cortically based cognitive tasks.78,80?86 Cognitive
interventions (e.g., cognitive-behavioral therapy), which target
common non-motor symptoms such as depression and anxiety also
may provide improvements in select cognitive domains (e.g.,
working memory, executive skills).75
Future research must address several key questions including
what specific training tasks positively impact real-world cognitive
abilities, what factors influence training outcomes, which cognitive
deficits in PD improve and whether this affects risk of cognitive
decline or dementia, whether cognitive improvements in one area
transfer to another, and what neurobiological mechanisms
underlie effects of cognitive interventions. Multi-component
programs targeting specific cognitive deficits may confer the
greatest benefit but require additional study. Large, long-term,
randomized controlled trials enrolling people with PD at all
disease stages, from early, or even at risk, to advanced stages, are
needed to determine whether specific types of cognitive training
can prevent, delay, or mitigate cognitive and functional decline.
Incorporating patient-centered outcomes will ensure that we are
meeting patient needs with regard to which cognitive functions
are most important for daily life. Apathy and fatigue, which can be
major impediments to participation in physical or cognitive
exercises or social activities for some patients with PD, also will
be important areas to target.
Nutritional interventions: can they help cognition in PD?
Good nutrition is essential for living well in general and with PD,
not only playing a role in optimizing general health and motor
strength but also potentially cognitive function. The relationship
between nutrition and cognition is an area of growing interest to
the PD community. In a large cross-sectional survey conducted by
the Parkinson Alliance (n = 1492), 93% of participants reported
that they believed that diet/nutrition was important in managing
their PD symptoms.87 Yet, only 11% of participants reported that a
healthcare professional offered specific dietary recommendations
to them. The majority of participants who followed a specific diet
?designed? their meal plans based on information obtained from
self-help resources (e.g., internet, magazines), family, and friends.
Moreover, while 63% of respondents perceived themselves as
eating a ?healthy? diet most of the time, there is a lack of
consensus as to what comprises a healthy diet for people with PD.
Discussions regarding nutrition in PD have typically focused on
topics such as protein and medication absorption, weight loss,
dysphagia, and gastrointestinal issues. However, there are
growing investigations of nutrients that may be associated with
increased or decreased risk of PD. Increased consumption of dairy
products88 and lower serum urate levels may be risk factors for
PD,89 whereas high intake of fruits, vegetables, and fish or use of
nicotine and caffeine may confer a lower risk of PD.90,91
Research on the relationship between nutrition and cognition in
general and in PD populations is increasing. Studies in non-PD
populations suggest that foods such as blueberries, cocoa, dark
chocolate, tea, and wine may protect against cognitive decline
(e.g., global cognition, verbal memory, executive skills, and verbal
fluency) over time.92?94 Specific dietary patterns (e.g.,
Mediterranean, DASH, and Mediterranean-DASH Intervention for
Neurodegenerative Delay (MIND)) may provide healthful effects in non-PD
groups.95?98 In one study, the MIND diet was associated with a
54% reduction in risk for AD. In a longitudinal cohort study,
adoption of more ?MIND-like? dietary patterns was associated with
less decline in global cognition, processing speed, and executive
function over a 4.7-year period, compared to ?traditional? patterns
of eating.95 Nutritional supplements (e.g., folate, vitamin B12) may
confer cognitive benefit, but dosages must be carefully
considered.99,100 Studies of nutritional interventions need to consider the
ways to best facilitate dietary behavior change and how to best
monitor dietary behaviors, food intake, and dietary supplements.
In addition, it will be important to examine potential confounders
such as psychosocial factors, concomitant exercise/physical
activity, presence of co-morbid medical or metabolic illnesses,
and genetic variants (e.g., ApoE) as well as methodological issues
such as the level of benefit from individual nutrients and/or foods
and use and interpretation of dietary pattern scores.101
To date, few studies have assessed interactions between
nutrition and cognition specifically in PD. A meta-analysis suggests
that higher homocysteine levels and lower folate and vitamin B12
levels were related to cognitive dysfunction in PD,102 though the
relationship of elevated homocysteine and PD cognitive
impairment is not fully established. Low plasma uric acid predicted
worse performance on cognitive tests in cross-sectional and
follow-up studies in PD.103
Higher vitamin D concentrations have been associated with
better performance on tests of verbal fluency and verbal memory
in non-demented PD patients, but this requires further study.104
Randomized controlled trials and longitudinal studies are
needed to determine the effect of individual food compounds,
supplements, and dietary patterns on cognitive functioning and
cognitive decline in PD. We need evidence-based nutritional
recommendations for enhancing cognitive function for people
with PD. We will need to distinguish between symptomatic and
potentially disease-modifying effects of nutritional choices.
Furthermore, we will need to define the optimal timing and
dosage of any dietary changes and who may benefit most from
nutritional interventions. Effective behavioral strategies for
facilitating healthy nutritional change will also be important.
PSYCHOSOCIAL CONSIDERATIONS REGARDING COGNITIVE
DECLINE IN PD
Care partners: burden, assessment, and support
Care partners or caregivers are an invaluable healthcare resource.
When caregivers are present, patients are less likely to move to
nursing homes.105 Caregivers also improve participation rates and
retention of people with PD in research studies, which helps
advance the path towards finding more effective therapeutics.106
Furthermore, many clinical trials for PDD require a caregiver in the
study inclusion criteria.
Informal caregivers are providers who supervise or assist with
instrumental and/or basic activities of daily living without pay to
someone who cannot do these activities independently due to
cognitive, physical, or psychological impairment. However,
caregivers provide much more than this formal definition states. They
often provide medical care including administration of
medications, emotional and social support, and advice on medical
decision-making. About 90% of men and 80% of women with PD
have caregivers during their physician visits,107 and most
caregivers are spouses.
Unfortunately, caring for a person with PD can lead to caregiver
burden and strain. When a person with PD experiences greater
cognitive impairment including dementia, neuropsychiatric
symptoms, and motor difficulties, health-related quality of life declines
and caregiver burden increases.108?110 Caregiver strain has been
linked to higher mortality.111 While there is strong evidence that
caregiving can be burdensome and negatively affect the
caregiver?s health and well-being, caregiving also can have
positive and rewarding aspects (e.g., taking pleasure in giving,
feeling purposeful, bringing people closer). Comprehensive,
multidimensional assessment of caregiver needs and strains are
vital in developing effective, targeted plans to address their
needs.112,113 Some assessments that can be used to gauge
caregiver needs and degree of burden include: interRAI home care
assessment, American Medical Association Caregiver
selfassessment questionnaire, Zarit Burden Interview, and
Multidimensional Caregiver Strain Index.
Current strategies to support caregivers center around three
main areas: education, psychosocial support, and
psychotherapeutic interventions. Education should start early at patient
diagnosis and maintain a ?patient-centered,? tailored approach.
Educational topics include PD symptoms and progression,
medication management, care coordination, resources,
communication with the healthcare team, and self-management
strategies. Psychosocial support provides an opportunity to discuss the
caregiving role with the patient and family. This can be achieved
via mental health providers (e.g., LICSW, psychologist) or PD
support groups. Specific psychotherapeutic interventions such as
Cognitive Behavioral Therapy, Relaxation Therapy, and Strength
Perspectives Therapy can aid the caregiver?s well-being. A
multidisciplinary team approach (e.g., physician, nurses, therapists,
social workers) helps to identify at-risk caregivers and provide
appropriate education, support, and referrals.
Despite existing therapeutic support and resources for
caregivers, there are several challenges to overcome. These include
sex disparities in caregiving (e.g., women with PD are less likely to
have informal caregivers then men) and the substantial financial
strain that can be associated with caregiving. Caregivers are
frequently at the forefront of providing medical history and
administering complicated medication regimens without
formalized education or support.
Future research should include developing ways to prevent or
lessen caregiver strain. Comparative-effectiveness research of
different education, skill-building and support resources for
caregivers of people with PD experiencing cognitive impairment
may be necessary to help allocate resources. Assessments of
current caregiver needs are necessary to inform health policy for
people with PD especially with cognitive impairment.
Decisional capacity considerations
Establishing decisional capacity is an important consideration in
the setting of cognitive impairment. Intact decisional capacity
includes the abilities to: understand relevant information,
appreciate the situation and its likely consequences, manipulate
information rationally (reasoning), and have evidence of a
choice.114 Capacity is important for consenting for medical/
surgical procedures, living independently, and making financial
decisions. Defining capacity is task-specific and situation-specific
and can be temporary and reversible. Investigations of capacity to
consent for research participation show that people with PD with
mildly impaired cognition have difficulty understanding medical
scenarios when compared to cognitively normal PD.115 With
greater cognitive impairment, appreciation and reasoning are also
affected. Specific cognitive domains that influence reasoning
capacity in PD include executive function and memory.116
Since even having MCI may affect capacity, it is important to
assess decision-making ability in both clinical and research
settings. Global cognitive tests such as the MoCA can provide
an index of the likelihood of impaired capacity. There also exist
tools specifically for capacity assessment including the MacArthur
Competence Assessment Tool for Treatment (MacCAT-T) and Aid
to Capacity Evaluation (ACE). Capacity assessments should include
inquiry about co-morbid medical conditions (e.g., hearing loss),
medications that could contribute to apparent diminished
capacity, physical and cognitive functional assessments, and
Altered decisional capacity in PD is under-recognized. It can be
difficult to detect in the context of established routines and may
not present itself until there is a novel demand or unfamiliar task.
However, performance on the MoCA in PD correlates with capacity
to understand discussions about goals of care.117 Training
healthcare professionals to recognize impaired decisional
capacity, to conduct an careful assessment, and to interpret the
findings is essential, as well as having a planned course of action
once it is clear that capacity is impaired. Occupational therapy can
be useful for evaluating patient abilities and safety at home and
when driving as well as for teaching skills to improve performance
and quality of life.
Current challenges include limited resources and training
available regarding capacity assessments for healthcare
professionals, research staff, and people with PD and their care partners.
There are no clear guidelines on how to systematically approach
decision-making capacity in PD (e.g., what is the role of clinical
judgment, at what time intervals should capacity be re-assessed).
Future research directions in PD include examining the
consequences of executive dysfunction on global
decisionmaking and changes in decision-making capacity over time.
Lastly, understanding the implications of capacity cut-off scores
are important for clinical trials participation, ethical and regulatory
oversight, and legal assessment.
QUESTIONS AND RECOMMENDATIONS
After discussion of the nine topics presented in this review,
conference participants were tasked with producing questions to
ascertain what recommendations they would give, as healthcare
providers, to a person at early, mid, or advanced PD stages
regarding maintaining their cognitive health and coping with
cognitive changes (Table 1). This feedback then generated the
recommendations listed by attendees, which include
nonpharmacological strategies (physical and cognitive exercise),
mental health wellness, psychosocial coping skills, and planning
(Table 3). These recommendations include several with a strong
evidence base (e.g., guidelines from the American College of
Sports Medicine and the American Heart Association for physical
exercise) and others with some literature support but requiring
further study and for which several are currently under study (e.g.,
cognitive training exercises, Mediterranean diet). The feedback
from attendees also included anecdotal, and often ?common
sense,? recommendations such as staying active socially, learning
coping strategies, taking ones time when doing tasks, seeking
help if feeling depressed or anxious, or taking care of the care
partner too. Overall, these recommendations can be incorporated
into the clinical care for people with PD and their care partners.
Exercise, diet, and cognitive training interventions should be
discussed with one?s healthcare providers for the best way to
implement them, and related health specialists such as physical
therapists, nutritionists, and neuropsychologists should be
consulted and part of the care team. Furthermore, future research on
outcomes of their utilization will help elucidate their impact and
From the group discussions, questions were developed by the
people with PD and their care partners focusing on what they
wished they had known from their healthcare provider regarding
cognitive changes (Table 2). These responses provide a unique
opportunity to have greater insight into what people with PD and
their care partners hope to achieve in their relationships with their
healthcare provider, throughout the entire course of PD. The views
of people with PD and their care partners suggest that they have a
desire for information at diagnosis regarding cognitive aspects of
PD, a topic that may not be readily discussed, as well as an interest
in being proactive about non-pharmacological strategies for PD
across all stages. In addition, the group recommendations, as
endorsed by people living with PD, include regular follow-up with
healthcare professionals for discussions about PD symptoms,
cognitive and mood assessments, and future planning and
referrals to allied therapists early and throughout the PD course
(Table 4). Direct input from people living with and affected by PD
offers an opportunity for the healthcare providers to hear what
matters to patients and their care partners, change the way that
care is provided from the moment of diagnosis, and empower
people with PD and their care partners to be actively engaged and
proactive with their care.
At present, there is only one Food Drug Administration-approved
medication for PDD in the United States, that is, the cholinesterase
inhibitor, rivastigmine, which was approved in 2006.
Evidencebased reviews in PD recommend rivastigmine as ?efficacious? for
the treatment of PDD, with an acceptable safety risk without need
for specialized monitoring.118 Other cholinesterase inhibitors,
donepezil (despite a large randomized controlled trial)119 and
galantamine, and memantine were rated as having ?insufficient
evidence? in the treatment of PDD, though they had acceptable
safety risk profiles without need for specialized monitoring.118
1. Exercise according to guidelines from American College of Sports Medicine and American Heart Association60,67,69,71
2. Stay active socially; for example, spend time with friends or join a support group
3. Engage in cognitive training exercises81,83,120
4. Learn coping strategies; for example, work with an occupational therapist or neuropsychologist on techniques for paying attention, remembering
things, or doing everyday tasks
5. Nutrition can affect cognition; for example, try a Mediterranean diet
6. Take your time when doing tasks
7. Let your family and friends know if you are having trouble
8. Seek help if feeling depressed or anxious120
Advanced Parkinson?s disease:
Keep following the above recommendations, PLUS:
1. Develop a highly structured daily routine that you follow
2. Consider the use of medication for cognitive impairment
3. Have an advanced directive in place (living will, treatments)120
4. For care partners?take care of your own health as well (see doctors as needed)111
5. For care partners?seek out support such as counseling
Recommendations based on conference participant feedback and references were noted
Information in this table has been previously published in the blog, Cognitive Problems in Parkinson?s Disease?Beth Vernaleo, PhD at www.
movementdisorders.org (March 2017).
1. Provide information at diagnosis regarding cognitive aspects of PD
2. Schedule a follow-up appointment or discussion a few weeks later to answer questions regarding PD
3. Be honest with regard to what changes in cognition can be expected
4. Refer to a neuropsychologist for baseline cognitive testing
5. Have cognition assessed regularly120
6. Refer to occupational therapy, physical therapy, speech language therapy, social worker, and nutritionist early and throughout the course of the
7. Evaluate patients for depression and anxiety as they can affect cognition120
8. Broach the subject of advance planning with patients and caregivers120
Recommendations based on PD community conference participant feedback and references were noted
Information in this table has been previously published in the blog, Cognitive Problems in Parkinson?s Disease?Beth Vernaleo, PhD at www.
movementdisorders.org (March 2017).
Other agents, particularly focused on the serotonin system, are
currently under study for PD dementia.65 Cholinesterase inhibitors,
MAO-B inhibitors, and stimulant-like medications have been
studied in PD-MCI, but trials have been limited by small sample
sizes, lack of uniform definitions, use of different outcome
measures, and negative results. Given the overall lack of
pharmacological therapies for PD cognitive impairment,
nonpharmacological therapies are of great interest. Studies of
nonpharmacological therapies such as physical exercise cognitive
training, and neuromodulation in PD cognitive dysfunction are
growing, though more rigorous study is needed. Recently, the
American Academy of Neurology updated the 2001 practice
guidelines for the diagnosis and management of MCI; while this
publication focused on MCI in AD, many of these
recommendations may extend to MCI in PD.120
In order to advance treatments for PD cognitive impairment
and promote ways to maintain cognitive health throughout
disease, several key issues need to be addressed. We will need to
identify strategies and therapies that address the full spectrum of
PD cognitive impairment with its heterogeneity of phenotype and
progression. We will need to develop and utilize statistical models
and predictive algorithms such as ones recently devised that
incorporate clinical features and genetics into scores for
individualized risk of subsequent dementia.121 We will need to
identify predictive biomarkers of cognitive impairment that can be
readily implemented in research and clinical settings. We will need
to develop and optimized measures for screening cognition in PD
and for use as primary and secondary outcomes in clinical
research trials. We will need a clear regulatory pathway for
pharmacological and non-pharmacological interventions for PD
cognitive impairment, including the PD-MCI stage, and for not
only symptomatic, but also disease-modifying agents that prevent
or slow cognitive decline.122 As these therapies come to fruition,
we will need to have appropriate insurance coverage for them.
Lastly, we will need better support and education regarding
cognitive changes for people with PD and their care partners, early
on in the disease as well as throughout their disease course.
Data availability Data sharing is not applicable to this article as no datasets were generated in this study.
We thank the Parkinson?s community for their inspiration in addressing this
debilitating unmet need. We also thank the Parkinson?s Disease Foundation for their
generous financial and logistical support for our gathering to discuss this issue. We
dedicate this manuscript to Reverend Donald Simmonds who made invaluable
contributions to Parkinson?s disease research, guiding many people with Parkinson?s
disease, care partners, clinicians, and researchers during his life. Parkinson?s Disease
Foundation Community Choice Research Award program.
Project conception, organization, and execution: J.G.G., B.A.V., R.C., N.D., R.D., T.E., J.E.
G., C.M., J.E., J.F., R.G., J.K., B.L., L.S., G.S., C.T., C.T., A.T., E.U., N.C., C.E., G.E., C.H., S.H., D.S.
Manuscript writing of the first draft: J.G.G., B.A.V., R.C., N.D., R.D., T.E., C.M. Manuscript
review and critique: J.G.G., B.A.V., R.C., N.D., R.D., T.E., J.E.G., C.M., J.E., J.F., R.G., J.K., B.L.,
L.S., G.S., C.T., C.T., A.T., E.U., N.C., C.E., G.E., C.H., S.H., D.S.
Competing interests: J.G.G. has received consulting/advisory board honoraria from
Acadia, Aptinyx, Biogen; grants/research support from Acadia, Biotie (site PI),
Consolidated Anti-Aging, National Institutes of Health, National Parkinson
Foundation, Michael J. Fox Foundation, Rush University; honoraria from American Academy
of Neurology, International Parkinson and Movement Disorder Society, MedEdicus;
and salary from Rush University Medical Center. B.A.V. has received salary from the
Parkinson?s Foundation. R.C. has received research funding from the Canadian
Institutes for Health Research (CIHR), Alberta Innovates Solutions, the Alzheimer
Society of Canada, University of Alberta Hospital Foundation, and National Institutes
of Health and is a site investigator for a pharmaceutical trial sponsored by Axovant
(back up site); served on the Scientific advisory board for Michael J. Fox Foundation,
the Parkinson?s Disease Foundation, Parkinson Canada, Editorial board for Frontiers in
Aging Neurosciences, Dementia and Geriatric Cognitive Disorders, Parkinsonism and
Related Disorders, and as safety monitor/scientific advisor for a Harvard University/Tel
Aviv University trial of DCTMS and a Western University investigator initiated
pharmaceutical trial. N.D. has received grant/research support from the National
Institutes of Health, Parkinson?s Foundation, Michael J. Fox Foundation, Parkinson
Council, Biotie, Abbvie and salary from the University of Pennsylvania. R.D. has
received grant/research support from the Michael J. Fox Foundation, the Parkinson?s
Unity Walk, the Veteran Affairs Administration, and the Parkinson?s Foundation;
consulting fees from the Michael J. Fox Foundation and the University of Delaware;
and salary from Rutgers University. T.E. has received grant/research support from the
National Institutes of Health, American Parkinson Disease Association and salary
support from Boston University. J.E.G. has received grant/research support from the
National Institutes of Health, Florida Department of Health, the Harry T. Mangurian
Foundation, and the Association for Frontotemporal Degeneration, serves as a
scientific advisor for Axovant, Biogen, Eisai, and Eli Lilly; receives licensing fees from
Pfizer, Lilly, Axovant, and Quintiles; conducts on-going clinical trials funded by
Biogen, Axovant, and Janssen, and serves on the editorial boards of
Neurodegenerative Disease Management, Alzheimer?s Disease and Associated Disorders, and Acta
Neuropathologica. C.M. has received grant/research support from The Michael J. Fox
Foundation, Canadian Institutes of Health Research, Movement Disorders Society;
National Institutes of Health; served as a consultant to Accorda Therapeutics; received
honoraria from EMD Serono, steering committee for National Parkinson Foundation;
and salary from the University Health Network. J. Edwards serves on Data Safety
Monitoring Boards on National Institutes of Health grants awarded to Posit Science
Inc. She previously served as a limited consultant to Posit Science Inc. in 2007, and
has worked as a consultant to Wilson Sonsini Goodrich & Rosati. J.F. has received
grant support from the Patient Centered Outcomes Research Institute, National
Institutes of Health, and salary from Mayo Clinic, Rochester, MN. J.K. serves as a site PI
for clinical trials sponsored by Novartis and Lilly and as a consultant to John Hancock.
L.S. has received grant/research support from the National Institutes of Health, the
Michael J. Fox Foundation, and Biotie/Acorda. G.S. has received grant support from
the Patient Centered Outcomes Research Institute and National Institutes of Health
and the Florida Department of Health; consulting fees from Novartis, the NFL
Concussion Settlement Program and book royalties; and salary from the University of
Florida, Gainesville. C.T. has received grant/research support from National Institutes
of Health; consulting/advisory board honoraria from UpToDate Inc., Viocare Food
Intake Advisory Board; and salary from Rush University Medical Center. C.A.T. has
received grant/research support from the National Institutes of Health and salary
support from Boston University. E.U. has received grant/research support from
Michael J. Fox Foundation, National Institutes of Health, Department of Veterans
Affairs; honoraria from the American Academy of Neurology; and salary from
University of Iowa and Department of Veterans Affairs. The remaing authors declare
no competing interests.
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