“Brain Mechanisms of Associative Memory Deficits in

Mild Cognitive Impairment Patients, with and without

Parkinson’s Disease”ByTazrina Alrazi (PhD student) The PCAN Lab

Parkinson’s Disease (PD)• Resting tremor• Rigidity• Bradykinesia

!!! Loss of Cognition!!!

Mild Cognitive Impairment (MCI)Normal Cognition

Mild Cognitive ImpairmentDementia:-Alzheimer’s dementia-Lewy body dementia-Parkinson’s dementia

Mild Cognitive Impairment (MCI)-MCI in PD (PD-MCI) is potentially important for early identification and intervention of PD patients who are at risk for developing dementia

-MCI encompasses all 5 cognitive domains

Executive functions

Visuo-spatial and visuo-perceptual functions

Memory

Attention

Language

Petersen RC. Mild cognitive impairment as a diagnostic entity. J Intern Med. 2004;256:183–94.

Epidemiology of PD-MCI• 26.7% (range 18.9–38.2%) of non-demented PD patients have PD-MCI

• Janvin et al. found 62% of PD-MCI patients converted to PDD over a 4-year period, compared with 20% of PD patients with normal cognition

• The frequency of conversion to PDD over a 4-year period was: multiple domain MCI (63%), single, non-memory domain MCI (69%), single domain, amnestic MCI (40%), andnormal cognition (20%)

Litvan I, Aarsland D, Adler CH, Goldman JG, Kulisevsky J, Mollenhauer B, et al. MDS Task Force on mild cognitive impairment in Parkinson's disease: Critical review of PD-MCI. Mov Disord. 2011;26:1814–24.

Pathophysiology of Cognitive Impairment in PD

Williams gray et. al. 2014

Supportive Material to the Hypothesis

Supportive Material

Dr. Monchi’s data submitted,2016

Supportive Material

Could lack of MTL compensation be an important marker of dementia in PD?

Candidate’s PhD Project“Brain mechanisms of associative memory deficits in mild cognitive impairment patients, with and without Parkinson’s Disease”

Hypothesis:

H1: PD, PD-MCI, non-PD-MCI, and healthy controls, as well as the PD/non-PD-MCI subgroups (amnestic/non-amnestic, single/multiple domain) will exhibit significantly different associative memory brain activation patterns.

H2: Lack of MTL compensation is an important marker of reduced cognitive performance in PD-MCI and non-PD-MCI.

H3: PD-MCI vs. HC will show less MTL activation; PD-non-MCI vs. HC will show more MTL activation.

Project Objectivesa) Characterize individuals with PD, PD-MCI, non-PD-MCI, and healthy controls according to their associative memory profiles;

b) Compare the associative memory and neural characteristic between the groups, PD, PD-MCI, PD-non-MCI, non-PD-MCI, and healthy controls;

c) Uncover the associative memory and neural characteristics within PD-MCI and non-PD-MCI sub-groups (amnestic/non-amnestic, single/multiple domain).

Study Tools

Associative memory task

Neuropsychological assessments

Functional MRI

Data Analysis

-ANOVA

-General linear model (FSL software)

-Correlation analysis

Study Design Participants:Parkinson’s disease, no mild cognitive impairment PD (non-MCI) (35)Parkinson’s disease with mild cognitive impairment PD-MCI (65)Mild cognitive impairment, no Parkinson’s disease MCI (non-PD-MCI) (65)Healthy Controls (age-matched to patients) HC (35)

Time point 1: Training on a full version of the task outside the scanner (day 1)Training on another mini version of the task right before scanning (day 2)Scanning with the main full version of the task (day 2) (collecting fMRI data)

Associative Memory“Associative memory is a form of episodic memory that has been accepted to be resource demanding, necessitating persons to learn individual items and the specific relationships between the items”

“Associative memory task is more challenging long term memory task than item memory”

Dennis NA, Turney IC, Webb CE, Overman AA. The effects of item familiarity on the neural correlates of successful associative memory encoding. Cogn Affect Beha Neurosci. 2015

Associative Memory TaskAssociative memory tasks demand high efficiency of the medial temporal lobe (MTL).

We hypothesize that reduced MTL BOLD (blood-oxygen-level-dependent contrast imaging) activity during associative memory task will correlate with reduced cognitive performance in our primary patient populations (PD, PD-MCI, non-PD-MCI) which will reflect significantly in comparison of the subgroups (amnestic/non amnestic; single/multiple domains). Do you like the pair?

Memorizing Phase Begins (1s)

Do you like the pair? (3s)

Unsure

Decision Making Phase Begins (1s)

Do you recall seeing these pictures? (3s)

Together

Together Not Together Never Seen

Together Not Together

Together Not TogetherNever Seen

Diagram of the Associative Memory Task 1st Run Encoding:

2nd Run Retrieval:

3rd Run, Encoding:4th Run, Retrieval:

3 s

16 TRIALS/BLOCK = 152 s

16 TRIALS/BLOCK = 120 s 16 TRIALS/BLOCK= 120 sD

ecis

ion

mak

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phas

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gins

Same modelSame model

Do y

ou li

ke th

e pa

ir?

Inta

ct p

air

Initial locked period: 1 sResponse time : 5 sAfter response locked period: 0.5s

Inter trial interval: 1 s

3 s 3 s 1 s

1 s

Mem

oriz

ing

phas

e be

gins

Do

you

reca

ll se

eing

thes

e pi

ctur

es?

3 s 3 s 3 s

Scra

mbl

ed p

air

Nev

er se

en p

air

Initial locked period: 1 sVariable response time : 7 sAfter response locked period: 0.5s

16 TRIALS/BLOCK = 120 s

16 TRIALS/BLOCK = 152 s16 TRIALS/BLOCK = 152 s

fMRI Data Analysis (Time 1)Event related General Linear Model (GLM) contrast analysis (1st analysis) :

-Scrambled pair vs. Intact pair (posterior MTL)

-Scrambled pair vs. Never seen pair (frontal and temporal lobe)

-Intact pair vs. Never seen pair

-Inter group analysis (between four groups)

Second analysis:

-Looking at the effect of repetition within encoding

(use block number as covariate in the GLM design matrix)

Possible Outcome

In particular, we predict that in PD-MCI/non-PD-MCI reduced BOLD activity in

the MTL will correlate with decreased global cognitive performance.

Within PD with or without MCI, there may be different patterns of neural activity

observed in fMRI with this associative memory task corresponding to different

cognitive profiles. Some profiles will look more like non-PD-MCI while others

will be more different.

Importance of This ResearchTo date, no other research group has looked into the neural patterns of activity

linked to associative memory to compare reduced cognitive performance in PD MCI and non-MCI which makes our research pioneering in this field.

This study will enlighten us on the importance of associative memory deficits in PD with respect to global cognitive deterioration, as well as the differences between the neural substrates linked to associative memory deficits in PD-MCI and non-PD-MCI.

This will ultimately yield intervention and potential treatment strategies tailored to different PD-MCI and non-PD-MCI patient subtypes, aimed at improving cognitive deficits and decelerating the decline.

Student UpdateCourses:

Neuro-1 (done)Neuro-2 (done)Neuroanatomy (done)Advanced Imaging (attended, done)Statistics (future goal)

Attends: Seminars in Movement Disorders, Cognitive Neurobiology, Hotchkiss Brain Institute (HBI) seminars, Dementia rounds, Neuroimaging Journal Clubs and lab meetings

PCAN Lab activities: Dancing with Parkinson Disease, Science in Theatre, Pedal for Parkinson’s…….

Collaborators• Guy Rouleau, M.D., Ph.D.

CHUM, Ste-Justine, Université de Montréal

At University of Calgary:

• Dr. Bruce Pike

• Dr. Eric Smith

• Dr. Zahinoor Ismail

• Dr. David Hogan

• Dr. Justyna Sarna

• Dr. Angela Haffenden Tourmaline Oil Chair in Parkinson’s Disease

Thank You

MRI Sequence• MRI Time point 1 and 2 (anatomical and functional MRI):

• The first MRI session (Visit B) will include, a 5 min anatomical T1 weighted (IR-FSPGR=GENERL ELECTRI), a 6 min T2 sagittal FLAIR sequence, four 6 min task-based (episodic memory task) T2* BOLD fMRI sequences, and a 10 min resting-state T2* BOLD fMRI sequence.

• The second MRI session (Visit C) will include a 5 min anatomical T1 weighted MP-RAGE, four 6 min task-based (executive task) BOLD T2* fMRI sequences, and an SE-PI diffusion weighted acquisition with 64 directions lasting 12 min.

• MRI Time point 3 (Visit B-alt)

• The MRI session will include, a 5 min anatomical T1 weighted

• MP-RAGE, a 6 min T2 sagittal FLAIR sequence, SE-PI diffusion weighted acquisition with 64 directions lasting 12 min, and a 10 min resting-state T2* BOLD fMRI sequence.

Epidemiology of Parkinson’s Disease Dementia

• PDD can affect up to 50% of patients 10 years after diagnosis and over 80% by 20

years

• Dementia risk is almost 3-5 times higher in PD patients than in age-matched healthy

controls

• Severely affects quality of life, independent activities of daily living, and

interpersonal relationships

Epidemiology of Parkinson’s Disease

• Parkinson’s disease (PD) is the second most common

neurodegenerative disorder in the world

• In North America, the prevalence of PD is 107-187 per 100,000

population

• The most alarming non-motor PD complication is dementia (PDD)

Mild Cognitive Impairment (MCI)

Mild cognitive impairment (MCI) includes a change in cognition reported by

the patient, client, or clinician, objective evidence of impairment in one or more

domains, preservation in functional abilities, and not demented.

Qualitatively, MCI differs from both normal aging and dementia and is a risk

factor for the development of dementia in PD

PD-MCI Frequency increases with:

More severe PD

Late disease onset

Lower educational levels

Litvan I, Aarsland D, Adler CH, Goldman JG, Kulisevsky J, Mollenhauer B, et al. MDS Task Force on mild cognitive impairment in Parkinson's disease: Critical review of PD-MCI. Mov Disord. 2011;26:1814–24.

Additional Analysis if Time PermitsInvestigation of how these patterns of activation correlate with the different

neuropsychological and neuropsychiatric measures.

How these patterns of activation correlate with medial temporal lobe volumetry.

Finally, comparison of the patterns of neural activation between time 1 and time 2 (18

months after time point 1), and study whether a certain pattern of neural activation at time

1 is predictive of faster cognitive decline.

The project is part of a larger longitudinal study looking into fronto-striatal circuit using

WCST, genotyping and anatomical analysis. If time permits I will do comparative

comparison with all these data collected via collaboration.

Mild Cognitive Impairment (MCI)Normal Cognition

Mild Cognitive ImpairmentDementia:-Alzheimer’s dementia-Lewy body dementia-Frontotemporal dementia-Parkinson’s dementia-Vascular dementia

R. C. PETERSEN CLASSIFICATION, 2004

Criteria for Amnestic-MCI (a-MCI)

• Memory complaint usually corroborated by an informant

• Objective memory impairment for age

• Essentially preserved general cognitive function

• Largely intact functional activities

• Not demented

Petersen RC. Mild cognitive impairment as a diagnostic entity. J Intern Med. 2004;256:183–94.

aMCI: Prodromal AD

PD-MCI PDD

• Old age

• Male

• Lower education

• Longer duration of PD

• Greater motor impairment

Mild Cognitive Impairment (MCI) Classification:

• MCI-Amnestic (single domain/multiple domain)

• MCI-Non Amnestic (single domain/multiple domain)

Petersen RC. Mild cognitive impairment as a diagnostic entity. J Intern Med. 2004;256:183–94.

Epidemiology of PD

• Parkinson’s disease (PD) is the second most common neurodegenerative disorder

in the world

• In North America, the prevalence of PD is 107-187 per 100,000 population

• The most alarming non-motor PD complication is dementia (PDD)

Epidemiology of PDD• PDD can affect up to 50% of patients 10 years after diagnosis and over 80% by 20

years

• Dementia risk is almost six times higher in PD patients than in age-matched

healthy controls

• Quality of life, independent activities of daily living, and interpersonal

relationships

New Concept

PD-normal PD-MCI PDD

Litvan I, Aarsland D, Adler CH, Goldman JG, Kulisevsky J, Mollenhauer B, et al. MDS Task Force on mild cognitive impairment in Parkinson's disease: Critical review of PD-MCI. Mov Disord. 2011;26:1814–24.