Webminar Cognitive Impairment

in Parkinson’s Disease

Oury Monchi, PhDParkinson, Cognition, Action and Neuroimaging Laboratory, Institut Universitaire de Gériatrie de Montréal, Département de Radiologie, Université de Montréal

Disclaimer

This presentation is provided for information purposes only and does not represent medical advice.  

If you have specific medically related questions, you should speak with a health care professional knowledgeable about Parkinson's disease.

Introduction

James Parkinson(1755-1828)

An essay on the shaking palsy 1817

Introduction Even though symptoms like hallucinations and

dementia had been reported in some patients with PD since 1882, the disease has been thought as nearly exclusively a movement disorders and the occurrence of cognitive deficit was overlooked for the next 100 years or so.

With the use of dopaminergic medication in the 1970’s, it was realized that ‘non-motor’ deficits can also occur in the disease and in some cases interfere significantly with the life of patients.

Plan of the presentation

Different cognitive profiles found in Parkinson’s Disease

Neural origins of cognitive deficits Their evolution and possible occurrence of

dementia The interaction with depression The effect of dopaminergic medication on

cognition Some future avenues and practical suggestions

I. Different cognitive profiles found in PD

First important studies on cognition in PD were published in the 1980’s (e.g. Taylor & Saint-Cyr, 1986), since then many others have been published

They suggest that most patients with PD exhibit cognitive changes. However they are not necessarily severe and can even be absent in some patients.

I. Different cognitive profiles found in PD

Executive deficits: ‘higher order processes’ that are used when:planning,problem-solving initiating a new task.

In daily life this may translate in finding it harder to make a decision, or to plan daily or weekly activities

It helps to give clues

I. Different cognitive profiles found in PD

Attention difficulties:

Problems in focusing or dividing attention in complex situations.

In real life, this may translate into difficulties in resisting to distraction or to perform more than one task at once.

It helps to focus on one goal or concept at a time

I. Different cognitive profiles found in PD

Visuo-spatial problems:

Problems in estimating distances,

discriminating and acting on visual information.

This can sometimes increase the risk of falls.

In real life this may translate in difficulties in orientation in an environment with complex visual stimuli, such as finding a specific isle in a supermarket.

At the later stages of the disease, illusions or little hallucinations are observed in some patients only.

I. Different cognitive profiles found in PD

Language dysfunction: word finding and naming deficits. Memory: Retrieving information that has already been

learned.

In PD the problem is mostly with recall, and not with pure semantic or encoding like can occur in Alzheimer’s disease. In PD patients with dementia these deficits are more severe.

Using a notepad can help IMPORTANT: Not all these symptoms are present in

patients, and great differences exist between them.

II. Neural origins of cognitive deficits in PD

The origins of cognitive deficits are not completely understood

Some cognitive deficits such as executive deficits are more common and originate from PD pathology (i.e. dopamine deficiency and fronto-striatal altered function).

The concept of bradyphrenia describes some cognitive deficits observed specifically in PD. It refers to a slowness in thinking and responding that could share similarities with bradykinesia.

Others such as memory problems are not necessarily found in the majority of patients and might occur from concurrent pathologies associated with aging.

II. Neural origins of cognitive deficits in PD

SOURCE: Yin and Balleine 2008.

II. Neural origins of cognitive deficits in PD

Since the 1990’s functional neuroimaging techniques such as fMRI

(functional Magnetic resonance Imaging) and PET (Positron Emission

Tomography) are helping us understand better the origins of

cognitive deficits

Neuroimaging Studies in our laboratory

II. Neural origins of cognitive deficits in PD

Wisconsin Card Sorting Task

Isolation of a cognitive cortico-striatal loop

including the ventrolateral PFC in the planning of a set-shift

Monchi et al., 2001: Journal of Neuroscience, editor’s choice Science and

Nature Reviews Neuroscience

fMRI WCST Results in Young Controls: Shift-planning

2ND ‘motor’ Cortico-BG loop (premotor cortex and putamen) involved in the execution of a shift

Monchi et al., Journal of Neuroscience, 2001

fMRI WCST Results in Young Controls: Shift-execution

fMRI WCST Results in PD-OFF and matched Controls: Shift-planning

Controls PD patients

Decreased activity in PD in the‘cognitive’ cortico-striatal loop during planning the set-

shiftMonchi et al., Journal of Neuroscience 2004Highlighted in ‘This Week in the Journal’

fMRI WCST Results in PD-OFF and matched Controls: Shift-execution

Controls PD patients

Decreased activity in PD in the‘motor’

cortico-striatal loop during ‘executing’ the

set-shift

Monchi et al., Journal of Neuroscience 2004Highlighted in ‘This Week in the Journal’

III. Evolution of cognitive deficits

Dementia does not occur at the early stages of Parkinson’s disease and usually only occurs after many years following diagnosis (if it does then it is another entity Lewy Body Dementia)

While age is the biggest predictor of dementia in PD, its prevalence in PD is higher than in the general population, and it is estimated to affect approximately 30% of PD patients

III. Evolution of cognitive deficits

At the early stages of the disease one can distinguish between patients with very little or no cognitive impairments and those with so called ‘Mild Cognitive Impairments’ MCI.

Patients with MCI have cognitive deficits in one or more domains of cognition, but they do not significantly impair their daily life (unlike dementia).

As a general rule deficits in only one domain of cognition (such as executive function) is not particularly predictive of dementia while deficits in multiple domains may require more attention.

fMRI WCST MCI vs. NON MCI OFF Shift Planning

Z = +4

5

2.5

T-stat

Z = +4

NON MCI MCI

Vs.

fMRI WCST MCI vs. NON MCI OFF

vs Control Matching

Shift Execution

NON MCI MCI

5.5

3.5

T-stat

Z = +30Z = +30

IV. Depression in PD

Depression is thought to be more common in PD than in the general population (more than twice the rate).

However, in most patients with depression in PD it is usually mild to moderate

Furthermore it is not clear that PD is correlated with all aspects of depression.

In contrast to major depressive disorder, suicidal tendencies or expressions of guilt and self-blame are rarely observed in PD patients.

IV. Depression in PD In PD depression can be confused with apathy or

fatigue which are common but distinct from depression

Apathy is a lack of motivation for goal-directed behaviour, consisting in a loss of initiative, interest and affect for goal-directed events.

Similarly to the general population cognitive deficits (especially those related to attention and executive deficits) correlate with depression, and it is not clear exactly what is their relationship.

V. Effect of dopaminergic medication

The effect of dopaminergic medication on cognitive deficits are still controversial, unlike for motor symptoms.

Some studies find some improvement, others find some worsening, and many find no effects.

We used neuroimaging to attempt to understand further why this may be the case

fMRI WCST PD ON vs. OFFSummary

Jubault et al. 2009, PLoS oneJubault et al, 2009, PlosOne

V. Effect of dopaminergic medication

SOURCE: Yin and Balleine 2008.

fMRI Young healthy adults

Ventral striatum Dorsal striatum

McDonald et al., 2011, Brain

Same task PD ON and OFF L-Dopa

McDonald et al., 2011,

Brain

V. Effect of dopaminergic medication

Other studies in literature

L-Dopa (e.g. Sinemet) seems to correlate with depression in PD but not dopaminergic agonist (e.g. Mirapex)

On the other hand it is possible to observe Impulse control disorders (compulsive buying, gambling, sexual disinhibition) after prolonged use of agonists but less so with L-Dopa

V. Effect of dopaminergic medication

These findings do NOT indicate that L-Dopa induces depression or that agonists create impulse control disorders

They suggest that in patients with a tendency for depression or for impulsivity, the use of L-Dopa or agonists respectively increase this trend.

The reason these studies are important is that MD’s/Neurologists not only have to take into account the evolution of the cardinal motor symptoms, as well as the possible occurrence of dyskinesia when determining the relative dosage of L-Dopa vs. agonists

But also the patient’s cognitive and behavioural profile

V. Effect of dopaminergic medication

V. Effect of dopaminergic medication

This is why patients with similar motor features and advancement in the disease may have different treatment

Studies are currently conducted in different laboratories including our own to better understand the complex relationship between cognition, behaviour and dopaminergic medications in PD

VI. Some future avenues and practical suggestions

Different groups are looking longitudinally for combinations of markers including anatomical and functional brain imaging, neuropsychological tests, and genotype that will help predict the possible occurrence of dementia in specific patients

This is important as if we can identify these early we can explore different therapeutic avenues to slow down cognitive decline

VI. Some future avenues and practical suggestions

These include different medication avenues such as Rivastigmine and cholinesterase inhibitor

BUT also non invasive stimulation Transcranial Magnetic Stimulation and Transcranial Direct Current Stimulation

And Programs of cognitive and physical stimulation

VI. Some future avenues and practical suggestions

Most importantly: As much as possible: keep active both mentally and physically, this will help slowing down both motor and cognitive decline

This does not mean running a marathon or solving advanced physics equations.

For example: Walking, slow dancing, yoga or Tai-Chi exercises, massages

Reading, playing games, listening to music Regularity is more important than intensity

MNI, McGill• Anne-Louise Lafontaine, MD,

MSc• Alain Ptito, PhD

CRIUGM/PCAN• Marie-Andrée Bruneau, MD, MSc• Clotilde Degroot, MSc• Benoît Kullmann, MD• Kristina Martinu, MSc•Atsuko Nagano, MD, PhD• Christophe Beditti, MSc• Beatriz Mejia, PhD• Thomas Jubault, PhD

• Antonio P. Strafella, MD, PhD Toronto Western Hospital & CAMH

Université de Montréal• Guy Rouleau, MD, PhD• Sylvain Chouinard, MD, MSc• Jean-Francois Gagnon, PhD

Collaborators and Funding