palermo unawareness of deficits in alzheimer’s disease role of the cingulate cortex
DESCRIPTION
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.TRANSCRIPT
Unawareness of deficits Unawareness of deficits in in
AlzheimerAlzheimer’’s Diseases DiseaseRole of the Cingulate CortexRole of the Cingulate Cortex
PhD Student: Palermo Sara Tutor: Amanzio Martina
Doctoral School in Experimental Neuroscience XXV cycle
AlzheimerAlzheimer’’s Diseases Disease
AlzheimerAlzheimer’’s Diseases Disease
Lack of awareness (1)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)
Lack of awareness (2)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)
Selected Volume of InterestSelected Volume of Interest
VOI Operational Definition (mean ± SD)Y= 6 ± 9 mm
Z = 40 ± 9 mm
Purpose of the studyPurpose of the study
1. Analyze a limited number of variables that may differentiate aware AD subjects from unaware ones;
2. Study the possible neural correlates of attention monitoring in Alzheimer’s disease subjects (AD) with lack of insight.
HypothesisHypothesis
PartecipantsPartecipants
PartecipantsPartecipants
No traumatic brain injuryNo history of stroke, neurological or psychiatric illnessNo lesion detectable on MRI T1 weighted
No mayor depression or dysthymia
No neurolepticsNo antidepressants, anxyiolytics or anticholinesterase drugs less then 15 days before neuropsychological evaluation
Convergent AssessmentConvergent Assessment
Design and ProceduresDesign and Procedures
Design and ProceduresDesign and Procedures
Neuropsychological AssessmentNeuropsychological 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)
Design and ProceduresDesign and Procedures
Psychiatric and Functional AssessmentPsychiatric and Functional Assessment
Apathy Evaluation Scale – Informant (Marin, 1996)Hamilton Depression Rating Scale (Hamilton, 1960)Hamilton Anxiety Rating Scale (Hamilton, 1959Mania 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)
Design and ProceduresDesign and Procedures
Response Inhibition Task AssessmentResponse Inhibition Task Assessment
Adapted from Braver et al. (2001)
Image acquisition Data analysis
T2-weighted images in EPI2500 ms Repetition Time60 ms Echo Time90° flip angle
→103 volumes parallel to the AC-PC commissure line
T1-weighted images in FFE25 ms Repetition TimeShortest Echo Time30° flip angle
→160 sagittal contiguous images
Brain Voyager QX
1. Coregistration in 3D high-resolution structural scan
2. Creation of a Talairach space 3. Creation of the volume time course 4. ACC RFX ROI analysis5. Correction for multiple comparison
Design and ProceduresDesign and Procedures
fMRI Procedure and SessionsfMRI Procedure and Sessions
Awareness Assessment ResultsAwareness Assessment Results
*
*
P<.000001*
*
Neuropsychiatric Assessment Results Neuropsychiatric Assessment Results
*
*
**
*P=.02
P=.003
P<.000001
P=.03
P=.0008
Neuropsychological Assessment Results (1)Neuropsychological Assessment Results (1)
*P=.04
Neuropsychological Assessment Results (2)Neuropsychological Assessment Results (2)
*P=.02
P=.03*
ResultsResultsAnalysis on postAnalysis on post--error response timeserror 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
But a strong suggestionBut a strong suggestion……..
Did the estimated number of errors correlate with the real number of errors they made?
aware patients r= 0.656 p= 0.018unaware patients r= 0.208 p= 0.626
fMRI resultsfMRI results
fMRI results for the ‘no-go’ minus ‘go’ conditions, in the comparison between aware minus unaware patients
x y z Cluster size tB Rostral prefrontal cortex [10] -7 54 5 539 2.6R Postcentral gyrus [2] 47 -23 49 1470 3R Middle temporal gyrus [39] 41 -71 25 3227 3.9R Anterior cingulate [24] 10 36 3 389 2.7R Anterior cingulate [24] 8 23 26 252 2.3L Temporal gyrus [21] -42 10 -34 261 2.4L Middle temporal gyrus [21] -54 3 -31 747 3.1L Superior temporal gyrus [38] -57 13 -16 627 3.5
R Putamen 22 4 3 454 2.7L Medial globus pallidus -11 2 1 2251 3.8
B Cerebellum, posterior lobe -3 -46 -36 1726 3.2R Cerebellum, anterior lobe 26 -53 29 398 2.9
fMRI resultsfMRI results
Sinopsis for the No-GO minus GO conditions, in the aware (on the right) and the unaware AD patients (on the left)
The clusters in the figure
represent the areas of greater
activation in the unaware
group in comparison to
the aware group.
fMRI results: fMRI results: groupsgroups’’ differential activationsdifferential activations
Percentage of lateralization of the BOLD signal in the Percentage of lateralization of the BOLD signal in the right hemisphere, for each of the two groupsright hemisphere, for each of the two groups
The fMRI data are consistent with those reported by Braver and colleagues (2001)
Braver’s sample Our AD sample
fMRI resultsfMRI results
No-GO minus GO conditions, in the comparison between aware minus unaware patients
Random effect (ROI) analysis performed on
the cingulate area
ConclusionsConclusions•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 postero-medial 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.
Future GoalsFuture 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.
AcknowledgmentsAcknowledgments