In early October, the Davis Phinney Foundation hosted a virtual conference.  Greg Pontone, MD, MHS, with Johns Hopkins Parkinson’s Disease Neuropsychiatry Clinic, spoke about cognition, mood, and the management of cognitive and mood changes in PD.  We at Stanford Parkinson’s Community Outreach listened to the talk, and are sharing our notes. 

Dr. Pontone spent some time distinguishing between cognitive changes most people are familiar with, that of Alzheimer’s dementia, and the cognitive changes seen in Parkinson’s disease.  Some people with Parkinson’s also develop dementia.

He shared medications used to treat dementia and highlighted those that are more effective for the cognitive changes commonly seen in Parkinson’s.  He was excited about a new medication he is researching which appears to be more effective than the medications currently on the market.

The two mood changes Dr. Pontone talked about were depression and anxiety.  He discussed the impact depression has on quality of life, and meditations to treat it.  He wrapped up his talk by noting how increased feelings of anxiety can be directly related to the wearing-off of medications.  

There are a few medications available that help to minimize symptom fluctuation due to ON-OFF periods or wearing-off of medications.  Whenever you are bothered by increasing symptoms or changes of your Parkinson’s symptoms, it is always a good idea to discuss the changes with your movement disorder specialist.

You can watch Dr. Pontone’s presentation on YouTube.

Note that the presentation begins after some technical difficulties 3:15 minutes into the recording.

On our website, the Stanford Parkinson’s Community Outreach team has gathered online articles, recorded webinars, and other resources about mood and cognition changes common in Parkinson’s.  Dr. Pontone’s talk primarily covered anxiety, depression and cognitive changes.  Another common mood issue in PD is apathy.  And other common cognitive changes are hallucinations and delusions.  Here are related links to the Stanford website for these issues:

• Anxiety
• Apathy
• Cognition 
• Depression
• Hallucinations and delusions

And now, on to my notes…

– Denise

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Cognition and Mood and How to Manage Them

Speaker: Dr. Greg Pontone
Davis Phinney Foundation Victory Counts Summit,
Albany, NY, October 3, 2020

Notes by Denise Dagan, Stanford Parkinson’s Community Outreach

Overview of cognitive impairment in Parkinson’s
Mild impairment – awareness of changes, like being less organized or slower processing, but able to find work-arounds and still get things done

• gradual decline in certain cognitive domains/abilities
• deficits are not sufficient to interfere significantly with functional independence, but difficulties on complex tasks may be present

Severe impairment – not everybody gets to this level of impairment

• impairment in two or more cognitive domains (e.g. organization and memory)
• decline from baseline with deficits that impair daily function

Cognitive functions/domains – the components that make up your mental abilities

• Executive function – organization, sequencing and planning, multitasking
  • often first cognitive function change noticed for those with PD
• Processing speed – how rapidly information is processed (bradykinesia = slowness of movement, bradyphrenia = slowness of thought)
  • bradyphrenia is most often noticed in the OFF medication state
  • bradyphrenia doesn’t mean there’s a major problem, but that it will take longer to get things done
• Attention – ability to sustain focus on a task, action or thought
  • cut out distractions to better concentrate on what you’re doing
• Memory – ability to store and retrieve new information
  • If you have major memory deficits, it indicates something more than Parkinson’s is happening in the brain.
• Visuospatial – conception of spatial relationships
  • Can cause problems with navigation, especially in unfamiliar places
• Language – ability to comprehend and express meaning, usually in words
  • Like memory, if you see changes in language, suspect secondary process happening in the brain

Impact of cognitive impairment on daily function – represents what happens for those with severe cognitive impairment that interferes with everyday life.  Doesn’t happen for everyone with Parkinson’s.  These changes are often reported by family members and caregivers because the person with this level of impairment may not notice or remember cognitive changes.

• Memory loss
  • Repeating same comment or question
  • Difficulty learning new information.  Example – When meeting new people, difficulty recalling their name or what you did when them
  • Long-term memory is usually more intact than new memories

• Difficulty performing familiar tasks (apraxia)
  • No longer able to use remote control, microwave, computer, etc.
  • Can’t organize medications
    
• Language deficits
  • Difficulty with word recall is a common age-related change to cognition
  • Forgetting simple words or using wrong or non-specific words, e.g., give me the ‘thing’
  • Difficulty following directions or conversations
    
• Time and place disorientation
  • Getting lost, especially in familiar places
    
• Poor judgement – probably an amalgam of impairment of several cognitive domains
  • Irresponsibility, forgetting appointments, ignoring risks (walking without cane or walker, etc)
  • Sometimes not cognitive impairment at all, but exhibiting stubbornness.  Evven though someone is told, it is better to swallow your pride than to sustain a fall, which can cause severe injury.

Executive dysfunction and slowed mental processing speed – this is something that is very common in people with PD

• Deficits in initiation, sequencing, planning and set shifting (going from one activity to another); impaired mental speed (bradyphrenia)
  
• Often the earliest detectible cognitive changes in Parkinson’s.  May manifest as still working through a to-do list at 3p, when you used to knock out everything by noon

AttentionExecutive dysfunctionProcessing speed
Influence of task demands in Parkinson’s

• “Let’s have tea!” study (Rochester et.al. Arch Phys Med Rehab, 2004).  Not the name of the study, but what Dr. Pontone’s team calls it.  Looked at how attentional demands during an everyday functional activity contributes to functional performance and gait disturbances.  Alternative description:  How multi-tasking affects ability to function optimally.
• Study
  • 20 mild to moderate people with Parkinson’s and 10 Controls
  • Four Tasks
    • Simple walking : walk from mock kitchen to mock living room
      
    • Dual motor : walk between rooms and carry a tea tray.  Everyone slowed a bit, but those with PD slowed a little more.
• Dual-cognitive : walk between rooms and recall a memory.  Everyone slowed a bit, but those with PD slowed a little more.
• Multiple motor-cognitive task : walk, carry a tea tray and recall a memory.  Everyone slowed a bit, but those with PD slowed much more.
• Results
  • Increased task complexity – slowed gait speed for those with PD
  • The takeaway: to function optimally those with PD need to focus on one thing at a time and avoid distractions

Parkinson’s and subcortical cognitive impairment

• Early pronounced executive dysfunction, attentional deficits, and slowed processing speed
• Language and memory are usually largely intact compared to cortical dementias under later in Parkinson’s progression
• Deviation from this pattern, e.g., ‘cortical’ deficits (memory, language, visuospatial relationships) could indicate a comorbidity (Alzheimer’s disease, cerebral vascular disease, or Lewy bodies) in the cortex.

File Cabinet Example of difference between a Parkinson’s brain with memory problems and an Alzheimer’s brain with memory problems.
Imagine your memory is like a file cabinet.  When you make a memory, you store it in that ‘file cabinet.’  When you recall a memory, it is like getting a file out of the file cabinet.

Two husbands, one with Parkinson’s and one with Alzheimer’s.  Both wives give their husbands a recipe to bake them a cake for their birthday in a couple days.

The husband with Alzheimer’s can’t encode the experience of having this conversation with his wife, nor where he put the recipe, because he has a primary cortical memory deficit.  No matter how hard he thinks or how many hint/reminders his wife gives him, he will not be able to remember the cake.

The husband with Parkinson’s will remember the conversation and where he put the recipe with a hint/reminder (cueing) from his wife.  He may be slow baking the cake, but he can do it.

Memory Impairment Parkinson’s vs. Alzheimer’s : retrieval vs. encoding – this is what’s going on in the brains of these two husbands

• Parkinson’s memory impairment = poor retrieval
  • recognition memory – normal (ability to recognize encoded memories)
  • free recall memory – some difficulty (ability to recall information unprompted/no cueing from memory)
  • benefits from cueing – yes
• Alzheimer’s memory impairment = impaired encoding
  • recognition memory – poor
  • free recall memory – poor
  • benefits from cueing – no

• Encoding = process of putting info into memory / Works fine in those with Parkinson’s.  If someone with Parkinson’s is not encoding memories, something more is going on.
  
• Retrieval = process of finding the info to remember / Some difficulty retrieving encoded memories in those with Parkinson’s.
  • Responds to cueing/reminding.
  • Slow cognitive processing means retrieving information or memories will take some time

Evidence based treatments for cognitive issues in Parkinson’s – treatments that have been rigorously, scientifically tested.

Treatments for mild/early stage cognitive impairment in Parkinson’s (and other disorders)There is no evidence that any of these medications are effective for mild cognitive impairment in any disorder partly because studies of these medications are 6-10 weeks.  Confirmation of effectiveness may be observed if long-term studies were done.

• Rivastigmine / Exelon – works on acetylcholine
  • Efficacy – insufficient evidence
  • Safety – acceptable risk without specialized monitoring
  • Practice implications – investigational
    
• Rasagiline / Azilect – increases amount of monoamines in the brain
  • Efficacy – insufficient evidence
  • Safety – acceptable risk without specialized monitoring
  • Practice implications – investigational
    
• Transcranial direct current stimulation – running electrical current through the brain.  Hope for effectiveness on executive function impairment for those with PD.
  • Efficacy – insufficient evidence
  • Safety – insufficient evidence
  • Practice implications – investigational
    
• Cognitive rehabilitation – effective for recovery from strokes and traumatic brain injury.  Researchers are learning how to best apply this technique for those with PD.
  • Efficacy – insufficient evidence
  • Safety – insufficient evidence
  • Practice implications – investigational

Currently at Johns Hopkins, Dr. Pontone is leading a study on Leviteracetam for treating early cognitive changes in those with Alzheimer’s.  There is also a pilot study for use of Leviteracetam for those with Parkinson’s.

The Holy Grail – Disease modifying treatments (Those that significantly slow or halt disease progression)

Treatments for severe cognitive impairment (dementia) in Parkinson’sThe first 3 on this list are acetylcholinesterase inhibitors, which in increase the amount of acetylcholine in your brain by keeping acetylcholine from being broken down.  They may cause nausea.

• Rivastigmine / Exelon 
  • Efficacy – efficacious
  • Safety – acceptable risk without specialized monitoring
  • Practice implications – clinical useful
    
• Donepezil / Aricept
  • Efficacy – insufficient evidence in Parkinson’s, but may be useful in PD
  • Safety – acceptable risk without specialized monitoring
  • Practice implications – possibly useful
    
• Galantamine / Razadyne
  • Efficacy – insufficient evidence in Parkinson’s, but may be useful in PD
  • Safety – acceptable risk without specialized monitoring
  • Practice implications – possibly useful
    
• Memantine / Namenda – Used in addition to first 3 on this list.  NMDA agonist works by decreasing overstimulation in the brain.
  • Efficacy – insufficient evidence in Parkinson’s, but may be useful in PD
  • Safety – acceptable risk without specialized monitoring
  • Practice implications – investigational

Action Items: what you can do to help cognitive function – these tips work whether you have PD, or not, especially exercise, sleep, and diet for everyone’s physical, mental, and emotional health.

• Reduce distractions
  
• Focus on one task at a time.  You may need to begin practicing mindfulness to develop this as a habit

• Talk to your doctor about depression.  Depression symptoms can mimic cognitive changes, but it is treatable.
  
• Exercise.  Most effective disease modifying therapy for Parkinson’s.  Improves both physical and cognitive function

• Prioritize quality sleep
  
• Eat a healthy diet
  
• Do cognitive/brain training (before you notice cognitive change), or rehabilitation (after you notice cognitive change)
  • Evolve – Brain Games and Cognitive Training ($1.99 on Google Play)
    
• Increase/maintain consistent social interaction
  • Social isolation causes emotional and intellectual deterioration
  • Develop your ‘bubble’ of people you trust not to give you covid and/or socialize via video chat or phone

Overview of mood disorders in Parkinson’sDepression in Parkinson’s disease – more prevalent in those with Parkinson’s than in those without PD.  Part of the reason is that the same brain changes that cause movement disorder affect the main pleasure chemical (dopamine), but also affect other monoamines (serotonin, norepinephrine) that are responsible for maintaining normal emotional function.  This affects not just your ability to be happy, but your ability to experience a normal range of emotion.

• Depressed mood
• Diminished interest or pleasure – no longer participating in activities they once enjoyed.  Those activities no longer provide pleasure.
• Decreased appetite/weight loss
• Insomnia or hypersomnia (sleeping too much)
  • Appetite and Sleep Patterns often change together in depression:
  • classic depression = insomnia and decreased appetite
  • variant = hypersomnia and binge eating
• Psychomotor agitation or retardation (slowing of movement due to depression)
  • Psychomotor Retardation in those with depression often manifests as a two second delay in responding to questions
• Decreased energy – difficult to tease out between being a symptom of Parkinson’s or depression
• Worthless or inappropriate guilt (even suicidal thoughts) – this is not a normal PD symptom
• Poor concentration or indecisiveness (even simple things like what to eat) – core feature of depression
• Recurrent thoughts of death or suicidal ideation – get help immediately.  
  • National Suicide Prevention Lifeline – 800-273-8255 (available 24 hours in English and Spanish)

Parkinson’s Foundation

• Parkinson’s Outcomes Project, a longitudinal look at which treatments produce the best health outcomes in people with Parkinson’s
• The impact of depression on quality of life is almost twice that of the motor impairments

Research Article:The longitudinal impact of depression on disability in Parkinson’s disease

Gregory M. Pontone, Catherine C. Bakker, Shaojie Chen, Zoltan Mari, Laura Marsh, Peter V. Rabins, James R. Williams and Susan S. Bassett

Objective: This study examined the association between physical disability and DSM-IV-TR depression status across six years

Methods: 137 adults with idiopathic PD.  A generalized linear mixed model with Northwestern Disability Scale score as dependent variable to determine the effect of baseline depression status on disability

Results: 43 depressed at baseline vs. 94 without depression.  Symptomatic depression predicted greater disability compared to both never depressed (p=0.0133) and remitted depression (p=0.0009) after controlling for sex, education, dopamine agonist use, and motor fluctuations.

Chart shows the Northwestern Disability Score by Visit over 8 years of a longitudinal study.  The study tracks participants ability to perform basic tasks, like walking, eating, and hygiene.  Lower scores are worse functioning, and higher scores are better functioning.  Each point represents a visit by an individual.  Study participants who have never been depressed function at a higher level than those who are depressed and show very slight decline in functioning.  Those who have active depression function at a lower level and their functioning has declined noticeable since onset of the study.

For those who treat depressive symptoms, their level of functioning returns to that of those who have never been depressed.

Evidence based treatments for Parkinson’s (Seppi K et.al. 2019)

• MDS review designation (2019) – pharmacological interventions
  • venlafaxine / Effexor – helps with chronic pain, so a good choice for those with PD who have pain
    • Efficacy – efficacious
    • Safety – acceptable risk with specialized monitoring
    • Practice Implications – clinically useful
      
  • nortriptyline, desipramine
    • Efficacy – likely efficacious, but likely because of the design of the studies with respect to those with Parkinson’s
    • Safety – acceptable risk with specialized monitoring
    • Practice Implications – possibly useful
      
  • SSRIs, others
    • Efficacy – likely efficacious, but likely because of the design of the studies with respect to those with Parkinson’s
    • Safety – acceptable risk with specialized monitoring
    • Practice Implications – possibly useful
      
• Non-pharmacological interventions
  • rTMS (repetitive transcranial magnetic stimulation), ECT (electroconvulsive treatments) brain stimulation treatments, and CBT (cognitive behavioral therapy)
    • Efficacy – insufficient evidence – likely efficacious
    • Safety – insufficient evidence
    • Practice Implications – possibly useful

Anxiety in Parkinson’s – often co-occurring with depression in Parkinson’s disease

• Persistent worry or panic
• Ruminating and ‘overthinking’
• Inability to relax
• Feeling restless or tense (sometimes pacing or moving around)
• Difficulty concentrating or indecisive
• Muscle tension or aches
• Trembling – increased tremor
• Sweating
• Diarrhea or upset stomach

Prevalence of anxiety and anxiety disorders in Parkinson’s

• Up to 55% have clinically significant anxiety symptoms
• 31% have an diagnosable anxiety disorder (e.g. DSM)

First Anxiety Disorder Onset Relative to Parkinson’s OnsetChart showing that many people with Parkinson’s disease have an anxiety disorder before being diagnosed with PD. Anxiety may be an early indicator individuals are at increased risk of developing Parkinson’s disease.

Dopaminergic medication ON-OFF fluctuations in Parkinson’sChart showing that a person with Parkinson’s disease and anxiety symptoms may experience increased anxiety (and worsening of other symptoms, increasing physical symptoms and mood fluctuations) as their Parkinson’s medications are wearing off.  Neurology specialists are getting better at minimizing the ON-OFF fluctuations caused by Parkinson’s medications wearing off with new extended release drugs, like Rytary.

Anxiety fluctuation with levodopa infusionChart showing study results tracking the level of anxiety experienced by both those with PD and their loved one’s observations of anxiety in the person with PD.  Anxiety was reduced both experienced and observed when the person with PD was given an infusion of dopamine.  As the dopamine wore off anxiety and observed anxiety increased.  
These studies demonstrate that not having enough dopamine can be the reason you are anxious.  That is also true of mood and depression.

Mood and motor fluctuation with levodopa infusionChart showing study results tracking mood and fluidity of movement in response to an infusion of levodopa.  Participants report low mood and difficulty moving prior to the infusion.  Both mood and fluidity of movement improves with infusion of dopamine.  Both mood and ease of movement decline as the dopamine wears off.

Doctors can use the same medications used for depression and anxiety in the general population for those who have Parkinson’s, but it is equally important to ensure that a person with Parkinson’s has adequate dopamine replacement therapy to treat depression, anxiety, and other mood disturbances.

Treatment of anxiety in Parkinson’s

• Optimizing motor function and addressing motor fluctuations is likely important
• Insufficient evidence to support medications for anxiety in Parkinson’s
• Cognitive Behavioral Therapy (CBT) for anxiety in Parkinson’s – open label and case reports are supportive
• Mindfulness-based therapies are promising – similar results to CBT, but a tool you can use the rest of your life
• Neuromodulation is an emerging option, e.g., rTMS, tDCS, and DBS (none in Parkinson’s have anxiety as primary outcome)

Action items – strategies for depression and anxiety in Parkinson’s

• Stay connected: Social isolation is the equivalent of smoking for mental health; it has both short and long term consequences
• Stay engaged: Participating in structured activities is exercise for the mind (hobbies, being social)
• Exercise: Physical activity has been shown to benefit mental health by lifting mood and decreasing stress and tension
• Sleep well: Poor sleep is both a risk factor for and symptom of depression and anxiety