Executive functions and the dysexecutive syndrome - Masud Husain Nuffield Dept Clinical Neurosciences & Dept Experimental Psychology, University ...
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Executive functions and the
dysexecutive syndrome
Masud Husain
Nuffield Dept Clinical Neurosciences & Dept Experimental Psychology, University of Oxford
What are executive functions?
They’re functions that are deployed when control needs to be exerted
§ Typically described as ‘supervisory’ or ‘controlling’
§ Deployed when a situation is novel or difficult
§ When you need to pay attention because there isn’t an automatic / habitual
response to the problem or the automatic response would be inappropriate
Example: If your friend’s mobile phone rings on the table, you don’t normally pick
it up and answer it, although you might under certain circumstances
§ When several cognitive processes need to be co-ordinated
§ Or when you need to shift from one type of process to another
Supervisory attentional system model
A general model to explain executive functions | Norman and Shallice
last
ished
Comes into play when
rtain
non-routine
e
or novel situations
ses Supervisory system arise, when automatic
ortex, responses might not
udies, be appropriate
her
ogy).
t
the
Tower
Test
etion
ese Sensory information Schemas Response systems
Current Biology
gle
ed Figure 1. The ‘Supervisory System’ model of executive functions.
d According to this model, behaviour is controlled by schemas, which may appropriately be trig-
ance, gered by incoming perceptual information in routine situations; but in non-routine situations, the
g executive functions of the Supervisory System are called upon to modulate their level of activity.
Orchestration of behaviour They’re functions deployed when control needs to be exerted § Initiate § Maintain / Sustain / Invigorate / Energize § Stop ongoing action / Inhibit prepotent response § Monitor consequences of behaviour / error monitoring § Switch to a different behavioural set / set shifting / mental flexibility § Working memory: manipulation of items in short term memory § Planning and prioritization § Multi-tasking § Social / emotional regulation § Strategic retrieval and selection of information from episodic memory
When executive function breaks down
Executive function Associated executive dysfunction Clinical presentation /
Behavioural disorder
Task initiation and energization Reduced self-generated behaviours Akinetic mutism, abulia, apathy. Reduced
Procrastination fluency
Sustain attention / maintain actions Poor ability to stay on task or sustain attention Distractible
Response inhibition Difficulty inhibiting behaviours Disinhibited
Acting ’without thinking’
Self or error monitoring Lack of awareness when errors or inappropriate responses Unaware and inability to learn from
are made mistakes
Cognitive flexibility Rigid thinking / stuck on thoughts, concepts or how to solve Inflexible / perseverative
Shifting behavioural set problems
Working memory Difficulty holding or manipulation information ”on-line” Difficulty following instructions or solving
required to perform tasks problems
Multi-tasking Difficulty co-ordinating activities simultaneously or Difficulty solving tasks that require multi-
sequentially tasking
Planning and prioritization Poor planning / organizational skills Difficulty making decisions or completing
Inefficient use of time tasks
Social / Emotion regulation Poor social skills, empathy, emotional lability, frustration Socially and/or emotionally inappropriate
with self / others
Strategic retrieval from episodic Incorrect or inappropriate recall of information for the Confabulation
memory context
Executive function tests
Executive function Cognitive measure Example of test
Task initiation and energization Verbal fluency Words beginning with F; designs joining
Non-verbal (e.g. design) fluency four dots on a grid in a minute
Sustain attention / maintain actions Sustained attention Continuous performance test
Response inhibition Inhibition of pre-potent response Go / No Go; Stroop; Hayling tests
Self or error monitoring Error detection and correction Perseveration on Wisconsin card sort test
Cognitive flexibility Set shifting Wisconsin card sort test
Shifting behavioural set Switch cost Trail making B
Working memory Verbal working memory forwards and backwards Digit span (forwards and reverse)
Visuospatial working memory forwards and backwards Corsi blocks (forwards and reverse)
Multi-tasking Optimal allocation of time Multiple errands; six elements tests
Planning and prioritization Planning and problem solving Tower of London / Tower of Hanoi tests
Social / Emotion regulation Ability to infer the thoughts of others Tests of theory of mind
Strategic retrieval from episodic Recall and recognition Word list learning; source memory tests;
memory autobiographical memory
Executive function tests
Stroop task
Congruent Incongruent
condition condition
GREEN BLUE
BLUE RED
RED GREEN
BROWN BLUE
Executive function tests
Executive function Cognitive measure Example of test
Task initiation and energization Verbal fluency Words beginning with F; designs joining
Non-verbal (e.g. design) fluency four dots on a grid in a minute
Sustain attention / maintain actions Sustained attention Continuous performance test
Response inhibition Inhibition of pre-potent response Go / No Go; Stroop; Hayling tests
Self or error monitoring Error detection and correction Perseveration on Wisconsin card sort test
Cognitive flexibility Set shifting Wisconsin card sort test
Shifting behavioural set Switch cost Trail making B
Working memory Verbal working memory forwards and backwards Digit span (forwards and reverse)
Visuospatial working memory forwards and backwards Corsi blocks (forwards and reverse)
Multi-tasking Optimal allocation of time Multiple errands; six elements tests
Planning and prioritization Planning and problem solving Tower of London / Tower of Hanoi tests
Social / Emotion regulation Ability to infer the thoughts of others Tests of theory of mind
Strategic retrieval from episodic Recall and recognition Word list learning; source memory tests;
memory autobiographical memory
Executive function tests
Stroop task Trail making test B
Congruent Incongruent
condition condition
GREEN BLUE
BLUE RED
RED GREEN
BROWN BLUE
Wisconsin Card Sorting Test
Colour Shape Number
Executive function tests
Executive function Cognitive measure Example of test
Task initiation and energization Verbal fluency Words beginning with F; designs joining
Non-verbal (e.g. design) fluency four dots on a grid in a minute
Sustain attention / maintain actions Sustained attention Continuous performance test
Response inhibition Inhibition of pre-potent response Go / No Go; Stroop; Hayling tests
Self or error monitoring Error detection and correction Perseveration on Wisconsin card sort test
Cognitive flexibility Set shifting Wisconsin card sort test
Shifting behavioural set Switch cost Trail making B
Working memory Verbal working memory forwards and backwards Digit span (forwards and reverse)
Visuospatial working memory forwards and backwards Corsi blocks (forwards and reverse)
Multi-tasking Optimal allocation of time Multiple errands; six elements tests
Planning and prioritization Planning and problem solving Tower of London / Tower of Hanoi tests
Social / Emotion regulation Ability to infer the thoughts of others Tests of theory of mind
Strategic retrieval from episodic Recall and recognition Word list learning; source memory tests;
memory autobiographical memoryExecutive function tests
Stroop task Trail making test B
Congruent Incongruent
condition condition
GREEN BLUE
BLUE RED
RED GREEN
BROWN BLUE
Wisconsin Card Sorting Test Tower of London
Colour Shape NumberExecutive function tests
Executive function Cognitive measure Example of test
Task initiation and energization Verbal fluency Words beginning with F; designs joining
Non-verbal (e.g. design) fluency four dots on a grid in a minute
Sustain attention / maintain actions Sustained attention Continuous performance test
Response inhibition Inhibition of pre-potent response Go / No Go; Stroop; Hayling tests
Self or error monitoring Error detection and correction Perseveration on Wisconsin card sort test
Cognitive flexibility Set shifting Wisconsin card sort test
Shifting behavioural set Switch cost Trail making B
Working memory Verbal working memory forwards and backwards Digit span (forwards and reverse)
Visuospatial working memory forwards and backwards Corsi blocks (forwards and reverse)
Multi-tasking Optimal allocation of time Multiple errands; six elements tests
Planning and prioritization Planning and problem solving Tower of London / Tower of Hanoi tests
Social / Emotion regulation Ability to infer the thoughts of others Tests of theory of mind
Strategic retrieval from episodic Recall and recognition Word list learning; source memory tests;
memory autobiographical memoryTheory of mind
Assessed for example using the Faux pas (breach of etiquette) test
Example:
Jill had just moved into a new apartment. Jill went shopping and bought some new curtains for her
bedroom. When she had just finished decorating her apartment, her best friend, Lisa, came over.
Jill gave her a tour of the apartment and asked, “How do you like my bedroom?”
“Those curtains are horrible” Lisa said, “I hope you are going to get some new ones!”
Q1 Did Lisa know the curtains were new?
Q2 Did someone say something they shouldn’t have?
For example of findings in patients with frontal lobe dysfunction, see Torralva et al (2009) BrainExecutive function tests
Executive function Cognitive measure Example of test
Task initiation and energization Verbal fluency Words beginning with F; designs joining
Non-verbal (e.g. design) fluency four dots on a grid in a minute
Sustain attention / maintain actions Sustained attention Continuous performance test
Response inhibition Inhibition of pre-potent response Go / No Go; Stroop; Hayling tests
Self or error monitoring Error detection and correction Perseveration on Wisconsin card sort test
Cognitive flexibility Set shifting Wisconsin card sort test
Shifting behavioural set Switch cost Trail making B
Working memory Verbal working memory forwards and backwards Digit span (forwards and reverse)
Visuospatial working memory forwards and backwards Corsi blocks (forwards and reverse)
Multi-tasking Optimal allocation of time Multiple errands; six elements tests
Planning and prioritization Planning and problem solving Tower of London / Tower of Hanoi tests
Social / Emotion regulation Ability to infer the thoughts of others Tests of theory of mind
Strategic retrieval from episodic Recall and recognition Word list learning; source memory tests;
memory autobiographical memoryNeuron
Review
Executive functions are not just ‘frontal’ 1
Neuron
Review
Frontoparietal system – ‘Mulitple demand’ system – identified across studies
A B
A HardB vs easy contrasts premotor cortex
premotor cortex intraparietal pre-SMA / anterior cingulate
intraparietal
sulcus
sulcus pre-SMA / anterior cingulate
Remembering words / non-words inferior frontal inferior frontal
sulcus sulcus
Arithmetic
anterior insula /
Spatial working memory frontal operculum
anterior insula /
C frontal operculum
Verbal working memory
C
Three different ‘conflictMDtasks’ language
Duncan (2013) Neuron
Figure 2. Multiple-Demand System in the Human Brain
(A) Activity pattern for hard minus easy contrast in tasks tapping multiple cognitive domains (top to bottom: remembering word/nonword strings, arithmetic,
spatial working memory, verbal working memory, and three versions of resisting response conflict).
(B) Mean hard minus easy activity pattern across all seven tasks. Generally bilateral activity has been captured by averaging across left and right hemispheres,
and projecting the resulting mean image onto the right. Included in the full multiple-demand (MD) pattern are a posterior strip of the lateral frontal surface, from
premotor cortex to the frontal operculum and anterior insula; an anterior-posterior strip extending along the inferior frontal sulcus; a dorsomedial strip extending
from pre-SMA to the dorsal part of the anterior cingulate; and activity along the length of the intraparietal sulcus. At least in visual tasks, accompanying activity is
generally seen in higher visual areas. Outside the cerebral cortex, activity is also seen in the medial cerebellum and elsewhere.
(C) Left hemisphere activity for two example participants, showing closely adjacent MD (blue; greater activity in memory for nonword stringsMD language
versus sentences)762
Fractionation of the ‘dysexecutive syndrome’
Stuss
Different cognitive deficits associated with different frontal lesions
2
Stuss (2011) J Int Neuropsyhcological Soc
Fig. 1. This figure illustrates the frontal cortical—basal ganglia—thalamic circuits, supporting the fractionation of the
frontal functional regions. Area 10 is not part of this circuitry, and is schematically presented in its polar location to suggest
its integrative functions. For an expanded explanation of the anatomical and functional connections of Area 10 with other
brain regions, see Gilbert, Gonen-Yaacovi, Benoit, Volle, & Burgess (2010) and Petrides and Pandya (2007). The figure
also serves as a summary of the findings. STG 5 superior temporal gyrus; Right/Left 5 cerebral hemispheres.c o r t e x 1 0 9 ( 2 0 1c8o) r3t2e 2x e3
1 0395( 2 0 1 8 ) 3 2 2 e3 3 5
Fractionation
1 8 ) 3 2 2 e3 35 of the ‘dysexecutive syndrome’ 329
Both behavioural and cognitive changes occur but not uniformly | Data from 828 patients
2
Fig. 2 e Frequency (%) of behavioral (left) and cognitive (right) dysexecutiveGodefroy
disorders in the m
et al (2018) Cortex
%) of behavioral
GREFEX cohorts (n(left)
¼ 828and cognitive
patients.). (right)
Note: TBI:dysexecutive disorders
Traumatic brain in the
injury; MS: main Sclerosis;
Multiple brain diseD
828 Cognitive
Mild patients.).Impairment.
Note: TBI: Traumatic brain injury; MS: Multiple Sclerosis; D: disease; MC
ysexecutive disorders in the main brain diseases in the
rment.
njury; MS: Multiple Sclerosis; D: disease; MCIa: amnesticconfirmatory test consensus criteria for bvFTD might need to be revisited
fficulties in their in the light of current research.62
of some features The evidence reviewed thus far indicates that no specific
sus prior to the cognitive profile seems to be associated with bvFTD early
mparing cohorts in the disease, although careful cognitive assessment will
Recently proposed reveal deficits, generally in the domains of executive
al FTD research function and episodic memory. With disease progression,
h operationalised the atrophy evolves to involve the anterior temporal
gnostic certainty: regions, and the pattern of deficits becomes less distinct
. Patients qualify from other FTD subtypes, notably semantic dementia.10
3
core behavioural
Behavioral variant frontotemporal dementia (bvFTD)
ial disinhibition,
c behaviours or Panel: International consensus criteria for bvFTD
europsychological
Neurodegenerative disease
dysfunction). A
clinical features
Associated with behavioural change and bilateral frontal atrophy
Must be present for any FTD clinical syndrome
Shows progressive deterioration of behaviour and/or cognition by observation or history
equivocal neuro-
finite” is reserved Possible bvFTD
pathogenic gene Three of the features (A–F) must be present; symptoms should occur repeatedly, not just
l) are currently as a single instance:
hological changes A Early (3 years) behavioural disinhibition
rchers.64 B Early (3 years) apathy or inertia
C Early (3 years) loss of sympathy or empathy
D Early (3 years) perseverative, stereotyped, or compulsive/ritualistic behaviour
E Hyperorality and dietary changes
with bvFTD can F Neuropsychological profile: executive function deficits with relative sparing of
europsychological memory and visuospatial functions
t personality and
Probable bvFTD
state examination
All the following criteria must be present to meet diagnosis:
ooke’s cognitive
A Meets criteria for possible bvFTD
90% of cases at
B Significant functional decline
e profile is one of
C Imaging results consistent with bvFTD (frontal and/or anterior temporal atrophy on
d visuospatial/
CT or MRI or frontal hypoperfusion or hypometabolism on SPECT or PET)
with bvFTD show
tious,67,68 and has Definite bvFTD
phenocopy cases. Criteria A and either B or C must be present to meet diagnosis:
entral diagnostic A Meets criteria for possible or probable bvFTD
agnostic criteria.64 B Histopathological evidence of FTLD on biopsy at post mortem
ination of specific C Presence of a known pathogenic mutation
Hayling test of
Exclusion criteria for bvFTD
n of the executive
Criteria A and B must both be answered negatively; criterion C can be positive for possible
help differentiate
bvFTD but must be negative for probable bvFTD:
ally abnormal in
A Pattern of deficits is better accounted for by other non-degenerative nervous system
al in phenocopy
or medical disorders
B Behavioural disturbance is better accounted for by a psychiatric diagnosis
odic memory has
C Biomarkers strongly indicative of Alzheimer’s disease or other neurodegenerative process
clinical diagnosis
–15%) of patients Additional features
esent with severe A Presence of motor neuron findings suggestive of motor neuron disease
ed that deficits in B Motor symptoms and signs similar to corticobasal degeneration and progressive
than previously supranuclear palsy
with bvFTD (ie, C Impaired word and object knowledge
similar memory D Motor speech deficits
episodic memory, E Substantial grammatical deficits
ty.71 The criterion
Criteria from Rascovsky et al.64 bvFTD=behavioural-variant frontotemporal dementia. FTD=frontotemporalThe breakdown of cognitive complaints at baseline con-
ts sisted of memory impairment (26/55, 47%), executive dys-
function (4/55, 7%), both (21/55, 38%) or neither memory
pants nor executive dysfunction (4/55, 7%). Hypertension, de-
Increasingly recognized that there are behavioural or
4
hic and clinical characteristics are presented in pression, sleep disorder and traumatic brain injury were
the most frequently mentioned conditions in the medical
Clinical groups
dysexecutive presentations in Alzheimer’s disease too
consisted of mildly impaired pa-
2736 | BRAIN 2015: 138; 2732–2749
mean MMSE scores ranging from 22 to 25 and history (Fig. 1B). Fifty-two per cent met international R. Ossenkoppele et al.
con-
e CDR Table
of !1. Patients andwithclinical
behavioural sensus criteria for possible behavioural variant FTD
1 Demographic characteristics according to diagnostic group
s disease (mean age: 64.7 " 8.8, median: 64.1, (Rascovsky et al., 2011). The majority of patients were
Behavioural/
1–83.5) and dysexecutivedysexecutive Alzheimer’s
Behavioural
disease close to the threshold of 53
Dysexecutive of 6 coreBehavioural
Typical behavioural/cogni-
Controls
variant presentation presentation Alzheimer’s variant FTD
: 69.2 " 8.5, median: 71.3, range: disease
Alzheimer’s 53.7–83.5) Alzheimer’s tive symptoms
disease required
Alzheimer’s diseasefordisease
a diagnosis of possible behav-
vely youngN at time of diagnosis 75 and more often 55*
ioural variant29*
FTD [2/6 (33%), 58
3/6 (22%)59
or 4/661(20%),
Agea 65.8 ! 8.5 64.7 ! 8.8 Fig. 1C], 69.2 and! 8.5had fewer behavioural
64.4 ! 8.6 symptoms
63.8 ! 6.8 compared
63.7 ! 8.1
% and 61%, respectively) 68.0
Sex (% male)
than female. Of 72.7 the 60.7 65.5 71.2 62.3
th behavioural Alzheimer’s disease to patients with behavioural variant FTD. Apathy was
Education (years)b 15.5 ! 3.1 and patients 15.7 ! 2.3 15.7 ! 2.7 15.8 ! 2.5 15.4 ! 3.2 17.3 ! 1.9
c more prominent than disinhibition and loss of empathy,
xecutive Alzheimer’s
MMSE disease, 59.5% and 40%
22.7 ! 5.6 22.5 ! 5.4 24.6 ! 3.3 22.5 ! 4.1 23.7 ! 5.4 29.4 ! 0.7
CDR d
0.9 ! 0.6 0.9 ! 0.4 while hyperorality
0.8 ! 0.3 and perseverative/compulsive
0.9 ! 0.5 1.1 ! 0.7 behaviours
0!0
east one APOE
GDSe
e4 allele, respectively.
3.4 ! 2.9 3.2 ! 2.8 were less3.7 ! 3.2 2.9 ! 2.1 5.0 ! 3.4 2.0 ! 2.6
f
common (Fig. 1D). Figure 1D and the
NPI 14.3 ! 16.8 15.4 ! 17.6 12.3 ! 18.1 7.0 ! 11.0 21.9 ! 20.0 2.7 ! 1.2
% APOE e4 carriersg 51.7 59.5
Neuropsychiatric
40.0
Inventory 72.1scores also 18.9 indicate that16.7 the be-
ral-predominant
APOE e4 + + / presentations
+ "/""g
6/25/29 of 6/19/17 havioural 2/8/15
profile of patients14/17/12 with behavioural
0/10/43 Alzheimer’s
3/7/50
r’s diseaseTIV (l) 1.60 ! 0.17 1.60 ! 0.15 disease was ! 0.19
1.61less profound than 1.59 !that
0.15 of 1.64 ! 0.16 with
patients 1.57 ! 0.14
behav-
Autopsy-confirmed 24 Figure 1 Clinical
17 features. Frequency12 of (A) first symptoms reported
8 by patients
21 and caregivers,- (B) self-reported medical conditions in the
esented initially with cognitive
PET/CSF biomarkers 41/22
difficulties (53%)
past history, (C) ioural
the number
28/18 of corevariant FTD. Neuropsychiatric
behavioural/cognitive
15/10 symptoms Inventory domains
26/29met of diagnostic
23/23 criteria for- behavioural variant FTD (bvFTD; Rascovsky
than with behavioural changes (25%, Fig. 1A).
et al., 2011), and (D) theseoften cited in typical
behavioural/cognitive features.Alzheimer’s disease such as anxiety,
Data are presented as mean ! SD unless indicated otherwise. Differences between groups were assessed using ANOVA with post hoc LSD tests [age, education, MMSE, CDR,
Geriatric Depression Scale (GDS), Neurophsychiatric Inventory (NPI) and total intracranial volume (TIV)], !2 (sex and APOE e4 status), and Kruskal-Wallis with post hoc Mann-
Whitney U-tests (number of APOE e4 alleles).
a
Dysexecutive Alzheimer’s disease 4 other groups, P 5 0.05.
b
Controls 4 patients, P 5 0.01.
Ossenkoppele et al (2015) Brain
c
Patients 5 controls, P 5 0.001; behavioural Alzheimer’s disease + typical Alzheimer’s disease 5 dysexecutive Alzheimer’s disease, P 5 0.05.
d
Patients 4 controls, P 5 0.001; behavioural variant FTD 4 dysexecutive Alzheimer’s disease, P 5 0.01.
e
Behavioural/dysexecutive Alzheimer’s disease + behavioural Alzheimer’s disease + dysexecutive Alzheimer’s disease + behavioural variant FTD 4 controls, P 5 0.05; behavioural
variant FTD 4 behavioural Alzheimer’s disease/dysexecutive Alzheimer’s disease + behavioural Alzheimer’s disease + typical Alzheimer’s disease, P 5 0.01.
f
Behavioural/dysexecutive Alzheimer’s disease + behavioural Alzheimer’s disease + dysexecutive Alzheimer’s disease + behavioural variant FTD 4 controls, P 5 0.05; behavioural
Alzheimer’s disease/dysexecutive Alzheimer’s disease + behavioural Alzheimer’s disease 4 typical Alzheimer’s disease, P 5 0.05; behavioural variant FTD 4 dysexecutive Alzheimer’s
disease + typical Alzheimer’s disease, P 5 0.05.
g
Behavioural/dysexecutive Alzheimer’s disease + behavioural Alzheimer’s disease + dysexecutive Alzheimer’s disease + typical Alzheimer’s disease 4 behavioural variant
FTD + controls, P 5 0.05; typical Alzheimer’s disease 4 dysexecutive Alzheimer’s disease, P 5 0.05.Progressive dysexecutive syndrome
Proposed recent criteria
5
§ Persistent, predominant and progressive decline >6 months in core executive function
(working memory, cognitive flexibility and/or inhibition)
§ Absence of predominant behavioural features (does not meet criteria for behavioural variant
frontotemporal dementia)
§ Evidence of impaired executive functions from patient and/or informat reports in conjunction
with cognitive assessment
Progressive dysexecutive syndrome with possible Alzheimer’s disease
§ Decreased CSF Aβ41-42 or A β 42/A β 40 ratio or abnormal amyloid PET
Progressive dysexecutive syndrome with definite Alzheimer’s disease
§ Meets criteria for possible AD plus one of: increase CSF P-tau, abnormal tau PET, autosomal
dominant familial AD mutation, post mortem confirmation of AD pathology
Townley et al (2020) Brain CommunicationsBehavioural/dysexecutive Alzheimer’s disease BRAIN 2015: 138; 2732–2749 | 2741
Frontal atrophy in behavioural or dysexecutive
Alzheimer’s can be fairly subtle 6
Alzheimer’s disease BRAIN 2015: 138; 2732–2749 | 2741
Behavioural AD Behavioural variant FTD
Dysexecutive AD Typical AD
Figure 3 Voxel-wise comparisons of grey matter volumes between healthy controls and the different diagnostic groups.
Contrasts were adjusted for age, sex, total intracranial volume, scanner type and centre. Results are superimposed on the SPM8 single-subject
template (left) and the study-specific DARTEL template (right), and displayed at P 5 0.001 uncorrected. Supplementary Table 1 includes the
coordinates of local maxima and their anatomical labels, T-values, P-values and cluster sizes.
Behavioural + Dysexecutive AD
Alzheimer’s disease and five with mixed behavioural/dysex- with behavioural variant FTD and the other with mixed
ecutive Alzheimer’s disease. The mean interval from time of behavioural variant FTD and progressive supranuclear
diagnosis to autopsy was 60.9 ! 23.8 months. All patients palsy. Several co-pathologies were observed in our neuro-
with behavioural/dysexecutive Alzheimer’s disease met pathological sample: cerebral amyloid angiopathy in 14/22
NIA-Reagan neuropathological criteria (Hyman and (64%, six mild, seven moderate and one severe), cerebro-
Trojanowski, 1997) for high-likelihood Alzheimer’s disease, vascular disease in 6/24 (25%, see legend of Table 2 for
Figure 3 Voxel-wise comparisons of grey matter volumes between healthy controls and the different diagnostic groups.
with frequent neuritic plaque scores (Mirra et al., 1991) specification), Lewy body disease in 10/24 (42%, four
Contrasts were adjusted for age, sex, total intracranial volume, scanner type and centre. Results are superimposed on the SPM8 single-subject
and Braak stage V (n = 4) or VI (n = 20) for neurofibrillary amygdala-predominant,
template (left) and the study-specific DARTEL template (right), and displayed at P 5 0.001 uncorrected.four transitional
Supplementary Tablelimbic and
1 includes thetwo
tangles (Braak and Braak, 1991; Braak et al., 2006). For diffuse neocortical),
coordinates of local maxima and their anatomical labels, T-values, P-values and cluster sizes. argyrophilic grain disease in 4/9
eight patients, Thal amyloid-b plaque stage (Thal et al., (44%, all limbic), and TARDBP in 1/12 patients (8%, un-
2002) was assessed. All had stage V and thus classified classifiable-limbic). Additionally, argyrophilic thorny astro-
for ‘high’ Alzheimer’s disease neuropathological change ac- cyte clusters (Munoz et Ossenkoppele
al., 2007) wereet alobserved
(2015) Brain
in three
cording to recently proposed NIA-AA guidelines
Alzheimer’s disease and five with mixed behavioural/dysex- (Montine patients, and one patient had a large pituitary
with behavioural variant FTD and the other with mixed adenoma.
etecutive
al., 2012). Of all patients,
Alzheimer’s two mean
disease. The had mixed dementia
interval withof
from time behavioural variant FTD and progressive supranuclear
Alzheimer’s
diagnosis todisease
autopsyandwasprogressive
60.9 ! 23.8 supranuclear
months. Allpalsy as
patients palsy. Several co-pathologies were observed in our neuro-
co-primary
formal
neuropathological diagnosis.
with behavioural/dysexecutive
criteria for possible behavioural
Both patients
Alzheimer’s
variant
disease met
FTD
met
during
Discussion
pathological sample: cerebral amyloid angiopathy in 14/22
NIA-Reagan neuropathological criteria (Hyman and (64%, six mild, seven moderate and one severe), cerebro-
lifetheand
e comparisons of grey matter volumes between healthy controls andTrojanowski,
additionally
different 1997) formet
diagnostic
our criteriaAlzheimer’s
high-likelihood
groups.
for dysexecutive
disease, Invascular
this retrospective study (25%,
disease in 6/24 we assessed the clinical,
see legend of Tableneuro-
2 for
Alzheimer’s disease. One patient was clinically diagnosed psychological, morphological and neuropathological14 | BRAIN COMMUNICATIONS 2020: Page 14 of 19
FDG PET in progressive dysexecutive syndrome 7
Figure 7 FDG–PET in executive predominant presentations versus amnestic, visual
Townley et al (2020) and language
Brain Communications
disease phenotypes. The FDG–PET scans from participants with dysexecutive predominate presentations (n ¼
amnestic predominate (n ¼ 110), (B) visual predominant (n ¼ 18), (C) and language predominant (n ¼ 7) present
each panel, the blue-black end of the spectrum encodes the t-score for a greater degree of hypometabolism in tatrophy. Frontal tau pathology differentiated behavioral/ distribution of tau pathology is closely related to clinical
dysexecutive vs amnestic AD variants and correlated with presentations of AD.14
severity of executive dysfunction. Our results provide ev-
idence of frontal involvement in behavioral/dysexecutive The brain regions with the highest discriminative accuracy for
AD and contribute to a framework in which the anatomical a diagnosis of behavioral/dysexecutive AD vs amnestic AD
Tau PET in progressive dysexecutive syndrome
tribution of Amyloid-β
Figure 3inTopographic
Amnestic and
Disease (AD)
Behavioral/Dysexecutive
Distribution of Amyloid-β in(b/d) Variants
Amnestic andofBehavioral/Dysexecutive
Alzheimer (b/d) Variants of Alzheimer
8
Amyloid PET [18F]AZD4694 Tau PET [18F]MK6240
(A) Strongest associations between [18F]MK6240
standardized uptake value ratio (SUVR) and
amnestic AD were observed in lateral temporal,
inferior parietal, precuneus, and posterior cingu-
late cortices. (B) Strongest associations between
[18F]MK6240 SUVR and behavioral/dysexecutive
AD were observed in the anterior cingulate, lateral
(A) Voxelwise regressions revealed that patients temporal, frontal insula, and orbitofrontal corti-
with amnestic AD had elevated amyloid-PET in the ces. (C) t Maps displaying significant differences
posterior cingulate, precuneus, inferior parietal, between patients with behavioral/dysexecutive
medial prefrontal, and occipital cortices as com- AD and patients with amnestic AD; after multiple
pared to cognitively unimpaired (CU) elderly. (B) comparisons correction with random field theory
Voxelwise regressions revealed that patients with (p < 0.001), no results remained significant. (D) t
behavioral/dysexecutive AD had elevated amy- Maps displaying significant differences between
loid-PET in the posterior cingulate, precuneus, patients with behavioral/dysexecutive AD and pa-
inferior parietal, and medial prefrontal cortices tients with amnestic AD. Behavioral/dysexecutive
compared to CU elderly. (C, D) No differences in subjects had greater tau-PET uptake in medial
the topography of amyloid-PET were observed prefrontal, anterior cingulate, and frontal insular
between patients with amnestic AD as compared cortices. t Statistical parametric maps were cor-
to patients with behavioral/dysexecutive AD. t rected for multiple comparisons using a random
Statistical parametric maps were corrected for field theory cluster threshold of p < 0.001. Age and
multiple comparisons using a random field theory sex were employed as covariates in each model.
cluster threshold of p < 0.001. Age and sex were CU = cognitively unimpaired.
employed as covariates in each model. Therriault et al (2021) Neurology
Neurology.org/N Neurology | Volume 96, Number 1 | January 5, 2021 e87
ology differentiated behavioral/ distribution of tau pathology is closely related to clinical
AD variants and correlated with presentations of AD.14
unction. Our results provide ev-Summary
Executive function and dysexecutive syndrome
§ Overview of executive functions and their breakdown to lead to cognitive deficits and
behavioural change
§ Not just ‘frontal’: importance of frontal networks connecting to other brain regions
§ Fractionation of the dysexecutive syndrome
§ Contribution to behavioural variant frontotemporal dementia (bvFTD)
§ Emerging interest and study of patients with a progressive dysexecutive syndrome
associated with Alzheimer’s disease
PDF of talk under Lectures tab at masudhusain.orgFigure 5 Accuracy of Imaging Biomarkers for Discriminating Behavioral/Dysexecutive (b/d)
Alzheimer Disease (AD) From Amnestic AD
Joseph Therriault et al. Neurology 2021;96:e81-e92
Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the
American Academy of Neurology.Figure 6 Association of Frontal Tau-PET Uptake With Executive Dysfunction in Alzheimer
Disease (AD)
Joseph Therriault et al. Neurology 2021;96:e81-e92
Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the
American Academy of Neurology.You can also read
