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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
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