Unawareness of deficits is a symptom of Alzheimer's disease that can be observed even in the early stages of the disease. The frontal hypoperfusion associated with reduced awareness of deficits has led to suggestions of the existence of a hypofunctioning prefrontal pathway involving the right dorsolateral prefrontal cortex, inferior parietal lobe, anterior cingulate gyri and limbic structures. Since this network plays an important role in response inhibition competence and patients with Alzheimer's disease who are unaware of their deficits exhibit impaired performance in response inhibition tasks, we predicted a relationship between unawareness of deficits and cingulate hypofunctionality. We tested this hypothesis in a sample of 29 patients with Alzheimer's disease (15 aware and 14 unaware of their disturbances), rating unawareness according to the Awareness of Deficit Questionnaire-Dementia scale. The cognitive domain was investigated by means of a wide battery including tests on executive functioning, memory and language. Neuropsychiatric aspects were investigated using batteries on behavioural mood changes, such as apathy and disinhibition. Cingulate functionality was assessed with functional magnetic resonance imaging, while patients performed a go/no-go task. In accordance with our hypotheses, unaware patients showed reduced task-sensitive activity in the right anterior cingulate area (Brodmann area 24) and in the rostral prefrontal cortex (Brodmann area 10). Unaware patients also showed reduced activity in the right post-central gyrus (Brodmann area 2), in the associative cortical areas such as the right parietotemporal-occipital junction (Brodmann area 39) and the left temporal gyrus (Brodmann areas 21 and 38), in the striatum and in the cerebellum. These findings suggest that the unawareness of deficits in early Alzheimer's disease is associated with reduced functional recruitment of the cingulofrontal and parietotemporal regions. Furthermore, in line with previous findings, we also found apathy and disinhibition to be prominent features of the first behavioural changes in unaware patients.

1. Unawareness of deficits
in
Alzheimer’s Disease
Role of the Cingulate Cortex
PhD Student: Palermo Sara
Tutor: Amanzio Martina
Doctoral School in Experimental Neuroscience
XXV cycle

2. Alzheimer’s Disease

3. Alzheimer’s Disease

4. Lack of awareness (1)
Unawareness is an organically based absence of insight
into physical, neurological or cognitive impairments
(McGlynn & Schacter, 1989; Starkstein et al., 2006)
This phenomenon ia a well-known feature of
Alzheimer’s Disease
(Migliorelli et al., 1995)
Unawareness of cognitive deficits may results in
delaying diagnosis, failure to initiate therapy and
conflict with caregivers
(Derouesné et al., 1999)

5. Lack of awareness (2)
Patients with early Alzheimer’s disease can show
impairments in the executive system
(Sebastian et al., 2006)
Unawareness in Alzheimer’s disease may result from a
greater impairment of the central executive system
(Lopez et al., 1994)

8. Selected Volume of Interest
VOI Operational Definition (mean ± SD)
Y= 6 ± 9 mm
Z = 40 ± 9 mm

9. Purpose of the study
1. Analyze a limited number of variables that
differentiate aware AD subjects from unaware ones;
may
2. Study the possible neural correlates of attention
monitoring in Alzheimer’s disease subjects (AD) with lack
of insight.

10. Hypothesis

11. Partecipants

12. Partecipants
No traumatic brain injury
No history of stroke, neurological or psychiatric illness
No lesion detectable on MRI T1 weighted
No mayor depression or dysthymia
No neuroleptics
No antidepressants, anxyiolytics or anticholinesterase
drugs less then 15 days before neuropsychological
evaluation

13. Convergent Assessment

14. Design and Procedures

15. Design and Procedures
Neuropsychological Assessment
Global Deterioration Scale (Reisberg et al., 1982)
Mini-Mental State Examination (Folstein et al., 1975)
Alzheimer’s Disease Assessment Scale (Rosen et al., 1984)
Token Test (Spinnler and Tognoni, 1987)
Trail Making Test (Reitan and Wolfson, 1994)
Attentional Matrices (Spinnler and Tognoni, 1987)
Behavioural Assessment of the Dysexecutive Syndrome
(Wilson et al., 1996)
Theory of Mind stories (Amanzio et al., 2008)

16. Design and Procedures
Psychiatric and Functional Assessment
Apathy Evaluation Scale – Informant (Marin, 1996)
Hamilton Depression Rating Scale (Hamilton, 1960)
Hamilton Anxiety Rating Scale (Hamilton, 1959
Mania Assessment Scale (Bech et al., 1978, Bech, 2002)
Disinhibition Scale (Starkstein et al., 2004)
Basic Activities of Daily Living (Katz et al, 1963)
Instrumental Activities of Daily Living (Lawton and Brody,
1969)

17. Design and Procedures
Response Inhibition Task Assessment
Adapted from Braver et al. (2001)

18. Design and Procedures
fMRI Procedure and Sessions
Image acquisition
Data analysis
T2-weighted images in EPI
2500 ms Repetition Time
60 ms Echo Time
90° flip angle
Brain Voyager QX
→103 volumes parallel to the AC-PC
2.
commissure line
1.
3.
4.
T1-weighted images in FFE
25 ms Repetition Time
Shortest Echo Time
30° flip angle
→160 sagittal contiguous images
5.
Coregistration in 3D high-resolution
structural scan
Creation of a Talairach space
Creation of the volume time course
ACC RFX ROI analysis
Correction for multiple comparison

19. Awareness Assessment Results
*
*
P<.000001
*
*

20. Neuropsychiatric Assessment Results
*
P<.000001
P=.0008
*
P=.02
*
P=.003
*
P=.03
*

21. Neuropsychological Assessment Results (1)
P=.04
*

22. Neuropsychological Assessment Results (2)
P=.03
*
P=.02
*

23. Results
Analysis on post-error response times
Any significant difference between groups:
t= -0.069
p=0.946
RTs after correct No-go vs RTs after incorrect No-go:
t= 0.100 p= 0.924

24. But a strong suggestion….
Did the estimated number of errors correlate with the real
number of errors they made?
aware patients
unaware patients
r= 0.656
r= 0.208
p= 0.018
p= 0.626

25. fMRI results
B Rostral prefrontal cortex [10]
R Postcentral gyrus
[2]
R Middle temporal gyrus [39]
R Anterior cingulate
[24]
R Anterior cingulate
[24]
L Temporal gyrus
[21]
L Middle temporal gyrus [21]
L Superior temporal gyrus [38]
x
-7
47
41
10
8
-42
-54
-57
y
54
-23
-71
36
23
10
3
13
z
5
49
25
3
26
-34
-31
-16
Cluster size
539
1470
3227
389
252
261
747
627
t
2.6
3
3.9
2.7
2.3
2.4
3.1
3.5
R Putamen
L Medial globus pallidus
22
-11
4
2
3
1
454
2251
2.7
3.8
B Cerebellum, posterior lobe
R Cerebellum, anterior lobe
-3
26
-46
-53
-36
29
1726
398
3.2
2.9
fMRI results for the ‘no-go’ minus ‘go’ conditions, in the comparison between
aware minus unaware patients

26. fMRI results
Sinopsis for the No-GO minus GO conditions, in the aware (on the right) and
the unaware AD patients (on the left)

27. fMRI results: groups’ differential activations
The clusters in
the figure
represent the
areas of
greater
activation in
the unaware
group in
comparison to
the aware
group.

28. Percentage of lateralization of the BOLD signal in the
right hemisphere, for each of the two groups

29. The fMRI data are consistent with those reported by Braver
and colleagues (2001)
Braver’s sample
Our AD sample

30. fMRI results
Random effect (ROI)
analysis performed on
the cingulate area
No-GO minus GO conditions, in the comparison between aware
minus unaware patients

31. Conclusions
•Our results show that unawareness of deficits in early
Alzheimer’s disease is associated with reduced functional
recruitment of the cingulofrontal and parietotemporal regions
during a response inhibition task.
•Unaware patients also show additional activations of posteromedial parietal areas which may reflect those compensatory
activations which contributed to the maintenance of the
performance in the response inhibition task.
•Moreover, our findings show that unaware patients are more
impaired in flexible thinking and that apathy and disinhibition
appear as the first significant behaviour changes in unaware
subjects.

32. Future Goals
•A combined study using event-related potential and fMRI to
analyse early error detection and its monitoring component
Ne/ERN in aware and unaware AD subjects;
• An analysis of the neuropsychological and anatomical
pathways in AD subjects with floating awareness (AQD:
14≤x≤32);
• an activation likelihood estimation (ALE) meta-analysis of
literature regarding unawareness of cognitive and behavioural
deficits in Alzheimer’s Disease.

33. Acknowledgments