Pre-clinical Cognitive Changes

Unit 1061 : NeuropsychiatryFrench National Institute of Health and Medical Research, Montpellier

Faculty of Medicine, University of Montpellier

http://u1061.montp.inserm.fr

Clinical and biological disease marker trajectories as a function of distance to clinical diagnosis

Ritchie et al. J Clin Psychiatry 2016

Research review PubMed 15 yrsBrain biomarkers and prospective cohort studies

152 articles; 96 cognitive tests

Significant differences between normal and pre-clinical participants :• divided attention and response inhibition• information processing time• working memory• verbal and non-verbal episodic memory• paired associate learning• visuospatial performance• spatial analysis (allocentric and egocentric)• semantic retrieval• frontal lobe (executive) functioning (inhibition, conceptual shifting,

strategy generation).

Visual + Verbal

MemorySemantic memory

Spatial analysis

Episodic MemoryWorking MemoryVisual Processing

Spatial functionsWorking MemoryExecutive functionsEpisodic Memory

LONGITUDINAL COHORT STUDIES

DIAGNOSIS AD

50 yr 45 40 35 30 25 20 15 10 5 0

FDG PETExecutive Functions (metabolism)

Visual Memory (RCBF)Processing speed

AMYLOID IMAGINGVisual memory

Executive functionsReaction time

Visual LearningVisual Attention

MRIMTL ATROPHY

Episodic MemoryWorking Memory

LanguageLearning

BIOMARKERSTUDIES

FMRIVisual AssociationsExecutive functions

Spatial memoryProcessing Speed

Visuospatial reasoning

MRI HIPPCAMPAL VOLUMES

Verbal FluencyEpisodic Verbal memory

Executive Functions

Pre-clinical cognitive performance (brain biomarkers and retrospective studies)

FIGURE 1 : Theoretical time-line to AD dementia diagnosis and observations of cognitive change

1) Validated (preferably by reference to longitudinal data) in relation to either preclinical or prodromal populations, Apolipoprotein status or amyloid levels2) Psychometric properties (re-test reliability, normality of score distributions, ceiling and floor effects)3) Cross-cultural suitability4) Availability of alternative forms (or ability to easily create fully alternative versions) 5) Availability of normative data 6) Limited practice effects

Criteria for Test Selection

• Flanker

• Coding – focused attention/ processing speed

RT, Information Processing Speed,Conceptual Shifting, Selective Attention

• Digit Span– auditory registration– Series of digits (2-9) repeated in reverse order

Dot counting – visual organization

Working Memory

• List Learning–rote verbal memory for unrelated information

• Story Memory – memory for conceptually related information

Verbal Episodic Memory

• Figure Copying

• Line orientation

Visuospatial Memory and Performance

• Picture Naming – expressive language– 10 drawings of common objects

• Verbal Fluency – semantic retrieval– Semantic and phonetic prompts

Language

FOUR MOUNTAINS

Allocentric spatial memoryBehavioral data correlated with hippocampal volume and cortical thickness precuneus and posterior cingulate gyrus. Cross-validated in UK and Italian MCI patients

Moodley et al. Hippocampus 2015

FOUR MOUNTAINS

Place Memory by CSF AD biomarker status

HC MCI- MCI+ AD ANOVA MCI- /+

11.1(2.1) 9.6(1.6) 5.8(2.3) 4.6(1.3) p<0.0001 0.0002

MMSE 0.8VOSP 0.5RAVLT delayed 1.0Semantic Fluency 0.8Trails B 0.02Digit Span 0.3

FAVORITESPAIRED ASSOCIATIONS

Learning task with high visual complexity, intraclass similarity and arbitrary and unique associationsAD deficits due to mediotemporal and temporocortical changesRegion subserving integration of episodic and semantic memoryWerheid et al. Cortex 2007Progressive decline across pre-clinical- prodromal trajectoryPapp et al. Clin Neuropsychol 2014

SUPERMARKET TROLLEYAllocentric and egocentric navigationTargets retrosplenial cortex and precuneus detecting early metabolic glucose and amyloid changes. Tu et al. Cortex 2015

Hippocampal damage not specific to ADSpecific to AD failure to translate between allocentric and egocentric orientationClinical diagnosis +voxel-based morphometry differented CN FTD AD - no signal RAVLT, Rey Figure, Digit SpanTu et al. Cortex 2015

SUPERMARKET TROLLEY