Webminar Cognitive Impairment in Parkinson’s Disease

1. WebminarCognitive Impairment in Parkinson’sDisease Oury Monchi, PhD Parkinson, Cognition, Action and NeuroimagingLaboratory, Institut Universitaire de Gériatrie de Montréal, Département de Radiologie, Université de Montréal

2. 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.

3. Introduction James Parkinson (1755-1828) An essay on the shaking palsy 1817

4. 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.

5. 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

6. 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.

7. 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

8. 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

9. 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.

10. 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.

11. 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.

12. II. Neural origins of cognitive deficits in PD SOURCE: Yin and Balleine 2008.

13. 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

14. NeuroimagingStudies in ourlaboratory

15. II. Neural origins of cognitive deficits in PD

16. Wisconsin CardSortingTask

17. Isolation of a cognitive cortico-striatal loop including the ventrolateral PFC in the planning of a set-shift fMRI WCST Results in Young Controls: Shift-planning Monchi et al., 2001: Journal of Neuroscience, editor’s choice Science and Nature Reviews Neuroscience

18. fMRI WCST Results in Young Controls: Shift-execution 2ND ‘motor’ Cortico-BG loop (premotor cortex and putamen) involved in the execution of a shift Monchi et al., Journal of Neuroscience, 2001

19. fMRI WCST Results in PD-OFF and matched Controls: Shift-planning Controls PD patients Decreasedactivity in PD in the‘cognitive’ cortico-striatalloopduring planning the set-shift Monchi et al., Journal of Neuroscience 2004 Highlighted in ‘This Week in the Journal’

20. fMRI WCST Results in PD-OFF and matched Controls: Shift-execution Controls PD patients Decreasedactivity in PD in the‘motor’ cortico-striatalloopduring ‘executing’ the set-shift Monchi et al., Journal of Neuroscience 2004 Highlighted in ‘This Week in the Journal’

21. 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

22. 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.

23. Shift Planning fMRI WCST MCI vs. NON MCI OFF NON MCI MCI T-stat 5 Vs. 2.5 Z = +4 Z = +4

24. Shift Execution fMRI WCST MCI vs. NON MCI OFF NON MCI MCI T-stat 5.5 vs Control Matching 3.5 Z = +30 Z = +30

25. 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.

26. 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.

27. 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

28. fMRI WCST PD ON vs. OFF Summary Jubault et al. 2009, PLoS one Jubault et al, 2009, PlosOne

29. V. Effect of dopaminergic medication SOURCE: Yin and Balleine 2008.

31. fMRI Young healthy adults Ventral striatum Dorsal striatum McDonald et al., 2011, Brain

32. Same task PD ON and OFF L-Dopa McDonald et al., 2011, Brain

33. 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

34. 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.

35. V. Effect of dopaminergic medication • 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

36. 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

37. 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

38. VI. Some future avenues and practical suggestions • These include different medication avenues such as Rivastigmine and cholinesteraseinhibitor • BUT also non invasive stimulation Transcranial Magnetic Stimulation and Transcranial Direct Current Stimulation • And Programs of cognitive and physical stimulation

39. 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

40. Collaborators and Funding • CRIUGM/PCAN • Marie-Andrée Bruneau, MD, MSc • Clotilde Degroot, MSc • Benoît Kullmann, MD • Kristina Martinu,MSc • AtsukoNagano, MD, PhD • Christophe Beditti, MSc • BeatrizMejia,PhD • Thomas Jubault, PhD • MNI, McGill • Anne-Louise Lafontaine, MD, MSc • Alain Ptito, PhD • Université de Montréal • Guy Rouleau, MD, PhD • Sylvain Chouinard, MD, MSc • Jean-Francois Gagnon, PhD Toronto Western Hospital & CAMH • Antonio P. Strafella, MD, PhD