Periodic Reporting for period 1 - UnaWireD (Anosognosia and delusions in the diseased brain)
Reporting period: 2022-09-01 to 2025-02-28
UnaWireD will provide the first in-depth investigation of two common symptoms of patients with dementia: UNAwareness of cognitive impairment (also indicated as "Anosognosia") and Delusions. It will test the hypothesis that these two symptoms share common brain mechanisms and depend on how the brain has been used and is WIREd. Although these symptoms impact significantly on a range of brain disorders, UnaWireD will focus on Alzheimer’s Disease (AD), in which the difference between patients who show the most severe form of these symptoms and patients who never present them is striking, yet largely unexplained. By combining multimodal imaging with experimental paradigms and extended clinical and biomarker characterisation, UnaWireD will:
a) establish whether anosognosia and delusions define a specific clinical subtype in AD;
b) determine if they are associated with specific premorbid personality profiles and cognitive vulnerability;
c) identify the brain networks specifically altered in the anosognosia/delusion AD subtype;
d) test if anosognosia, like delusions, is associated with an imbalance in the brain neurotransmitter dopamine.
UnaWireD will deliver a new framework to study the interplay between the spared and damaged brain in the origin of productive symptoms in dementia. By doing so, it will open a window towards a better understanding of the uniquely human abilities of self-reflection and consciousness.
a) establish whether anosognosia and delusions define a specific clinical subtype in AD;
b) determine if they are associated with specific premorbid personality profiles and cognitive vulnerability;
c) identify the brain networks specifically altered in the anosognosia/delusion AD subtype;
d) test if anosognosia, like delusions, is associated with an imbalance in the brain neurotransmitter dopamine.
UnaWireD will deliver a new framework to study the interplay between the spared and damaged brain in the origin of productive symptoms in dementia. By doing so, it will open a window towards a better understanding of the uniquely human abilities of self-reflection and consciousness.
After having obtained ethical approval, we commenced and are now in an advanced phase of the recruitment of patients and healthy controls (HC), in whom we are performing cognitive and personality testing (behavioural data) and collecting structural and functional MRI (fMRI) data.
Preliminary correlation and regression analyses have been performed on the behavioural data so far collected from patients and HC to relate premorbid personality and cognitive reserve to anosognosia and delusions. We found that AD patients with anosognosia have a lower premorbid tendency to reflectiveness and lower cognitive reserve. This preliminary result supports the hypothesis proposed in UnaWireD: Individuals who, in the course of their life, have engaged in more reflective thinking seem to demonstrate greater awareness of their cognitive impairment, therefore reflection has a potentially protective role against anosognosia in individuals with AD.
Resting-state fMRI (rsfMRI) data collected so far have been preprocessed using independent component analysis at the single subject level. Task-based fMRI data collected so far have also been preprocessed and analysed at the single-subject level. Preliminary fMRI group analyses have been performed in the HC group only to compare results with literature concerning error monitoring and self-reflection. Comparisons between patients with/without anosognosia and/or delusions relative to HC will be performed when we have reached a minimum sample size of 15 patients for each group with/without each symptom. The preliminary analyses performed on data collected so far suggested analysing in a novel way previously collected (before UnaWireD) rsfMRI data to test whether AD patients with anosognosia have an altered balance between the Default Mode Network (DMN) and the Salience Network (SN). We found that anosognosia was associated with a weaker functional connectivity within the DMN and stronger functional connectivity within the SN, suggesting that a dysregulation of the functional connectivity of the DMN and SN may lead to anosognosia. These rsfMRI findings allowed us the publication of peer-reviewed papers.
We also expanded the study of delusions and other behavioural disturbances into previously collected imaging data from patients with frontotemporal dementia, showing that psychotic symptoms, such as delusions, are mainly correlated to functional, rather than structural, brain changes in these patients (this also led to a peer-review publication).
We conducted a review about the brain correlates of anosognosia in Parkinson’s (PD) and Huntington’s Diseases (HD), the two model diseases of dopaminergic imbalance, showing the involvement of regions of the SN and fronto-parietal network to be associated with unawareness in PD patients.
Finally, we analysed structural MRI data to correlate the spatial patterns of Grey Matter Volume (GMV) alterations of aware or unaware AD patients with specific neurotransmitter systems. We found the involvement of serotonin and glutamate receptors in aware patients, and of dopamine transporter and receptors in unaware patients. Although exploratory, these findings confirm the involvement of dopamine in the origin of anosognosia which is one of the main hypotheses of UnaWireD.
Preliminary correlation and regression analyses have been performed on the behavioural data so far collected from patients and HC to relate premorbid personality and cognitive reserve to anosognosia and delusions. We found that AD patients with anosognosia have a lower premorbid tendency to reflectiveness and lower cognitive reserve. This preliminary result supports the hypothesis proposed in UnaWireD: Individuals who, in the course of their life, have engaged in more reflective thinking seem to demonstrate greater awareness of their cognitive impairment, therefore reflection has a potentially protective role against anosognosia in individuals with AD.
Resting-state fMRI (rsfMRI) data collected so far have been preprocessed using independent component analysis at the single subject level. Task-based fMRI data collected so far have also been preprocessed and analysed at the single-subject level. Preliminary fMRI group analyses have been performed in the HC group only to compare results with literature concerning error monitoring and self-reflection. Comparisons between patients with/without anosognosia and/or delusions relative to HC will be performed when we have reached a minimum sample size of 15 patients for each group with/without each symptom. The preliminary analyses performed on data collected so far suggested analysing in a novel way previously collected (before UnaWireD) rsfMRI data to test whether AD patients with anosognosia have an altered balance between the Default Mode Network (DMN) and the Salience Network (SN). We found that anosognosia was associated with a weaker functional connectivity within the DMN and stronger functional connectivity within the SN, suggesting that a dysregulation of the functional connectivity of the DMN and SN may lead to anosognosia. These rsfMRI findings allowed us the publication of peer-reviewed papers.
We also expanded the study of delusions and other behavioural disturbances into previously collected imaging data from patients with frontotemporal dementia, showing that psychotic symptoms, such as delusions, are mainly correlated to functional, rather than structural, brain changes in these patients (this also led to a peer-review publication).
We conducted a review about the brain correlates of anosognosia in Parkinson’s (PD) and Huntington’s Diseases (HD), the two model diseases of dopaminergic imbalance, showing the involvement of regions of the SN and fronto-parietal network to be associated with unawareness in PD patients.
Finally, we analysed structural MRI data to correlate the spatial patterns of Grey Matter Volume (GMV) alterations of aware or unaware AD patients with specific neurotransmitter systems. We found the involvement of serotonin and glutamate receptors in aware patients, and of dopamine transporter and receptors in unaware patients. Although exploratory, these findings confirm the involvement of dopamine in the origin of anosognosia which is one of the main hypotheses of UnaWireD.
So far we have focused on anosognosia, while continuing recruiting participants and following them up longitudinally. We have studied the neural correlates of anosognosia with novel techniques and for the first time explored its association with premorbid personality traits.
One of the most significant achievements of our preliminary data is the demonstration that anosognosia is associated with an imbalance between the activity and reciprocal connections of three large-scale brain networks, namely the salience network (SN), the default mode network (DMN), and the fronto-parietal network (FPN). Even though UnaWireD hypotheses were focused on the DMN and SN, finding the involvement of the FPN (with divergent patterns of posterior/decreased versus anterior/increased functional connectivity) perfectly fit with cognitive models of awareness and unawareness that had been speculatively suggested in the literature but never experimentally demonstrated. We hypothesise that the FPN could work as an attentional modulator of the DMN-SN balance depending on whether the task demand is internal or external. An imbalance of these networks’ connectivity may be the basis of anosognosia in AD patients.
Our preliminary results demonstrate also an association between the tendency to reflect and the awareness of cognitive deficits in AD patients supporting the hypothesis that lifelong personality traits, such as reflection, may influence the clinical presentation of neurodegenerative diseases like AD. Individuals who engage in more reflective thinking seem to demonstrate greater awareness of their cognitive impairments. These findings underline the significant role of reflectivness as a potentially protective factor against anosognosia, and may be translated into the development of commercialisable prevention tools to be used in healthy individuals to ‘protect’ them from anosognosia and delusions.
After UnaWireD commenced in September 2022, two new disease-modifying therapies for Alzheimer’s disease have been approved by the FDA. One of these was approved for comercialisazion in the EU by EMA very recently. At this pivotal moment, as we approach a new era of treatment for Alzheimer’s disease, the development and implementation of cost-effective diagnostic tools enabling the timely and accurate identification of individuals most likely to benefit from emerging pharmacological interventions has become imperative. A research projects like UnaWireD aimed at investigating common symptoms of AD cannot disregard the necessity of contextualizing these phenomena within the evolving framework of therapeutic eligibility and regulatory criteria for the prescription of these novel agents.
One of the most significant achievements of our preliminary data is the demonstration that anosognosia is associated with an imbalance between the activity and reciprocal connections of three large-scale brain networks, namely the salience network (SN), the default mode network (DMN), and the fronto-parietal network (FPN). Even though UnaWireD hypotheses were focused on the DMN and SN, finding the involvement of the FPN (with divergent patterns of posterior/decreased versus anterior/increased functional connectivity) perfectly fit with cognitive models of awareness and unawareness that had been speculatively suggested in the literature but never experimentally demonstrated. We hypothesise that the FPN could work as an attentional modulator of the DMN-SN balance depending on whether the task demand is internal or external. An imbalance of these networks’ connectivity may be the basis of anosognosia in AD patients.
Our preliminary results demonstrate also an association between the tendency to reflect and the awareness of cognitive deficits in AD patients supporting the hypothesis that lifelong personality traits, such as reflection, may influence the clinical presentation of neurodegenerative diseases like AD. Individuals who engage in more reflective thinking seem to demonstrate greater awareness of their cognitive impairments. These findings underline the significant role of reflectivness as a potentially protective factor against anosognosia, and may be translated into the development of commercialisable prevention tools to be used in healthy individuals to ‘protect’ them from anosognosia and delusions.
After UnaWireD commenced in September 2022, two new disease-modifying therapies for Alzheimer’s disease have been approved by the FDA. One of these was approved for comercialisazion in the EU by EMA very recently. At this pivotal moment, as we approach a new era of treatment for Alzheimer’s disease, the development and implementation of cost-effective diagnostic tools enabling the timely and accurate identification of individuals most likely to benefit from emerging pharmacological interventions has become imperative. A research projects like UnaWireD aimed at investigating common symptoms of AD cannot disregard the necessity of contextualizing these phenomena within the evolving framework of therapeutic eligibility and regulatory criteria for the prescription of these novel agents.