The goal of the K01 candidate is to establish an independent research program on neurodegenerative dementias, with the main focus of improving public health through the advancement of multi-modal imaging capabilities to diagnose Alzheimer's disease (AD) early on and monitor its progression. Because self- appraisals guide much of human behavior, inaccurate judgments shown by many AD patients (i.e., impaired self-awareness or anosognosia) can yield serious consequences, and poses a major problem in the diagnosis, treatment and care of the patient. Despite the impact of anosognosia on patients and their caregivers, our knowledge of its clinical and neurological correlates as well as prognostic value is poorly understood. The research proposed herein specifically aims to investigate the neural underpinnings of memory self-awareness and the progressive dysfunction of these systems that underlie the loss of self-awareness with AD progression. Specifically, we propose to probe the mechanistic underpinnings of self-awareness of memory utilizing an innovative and novel combination of multi-modal imaging techniques. Our preliminary data, using functional connectivity analysis (as assessed with resting state fMRI, fcMRI) provides further proof that the posterior cingulate and medial prefrontal cortex, two major hubs in the default mode network (DMN), are crucial for accurate memory self-appraisal. Here, we propose to combine fcMRI with a novel fMRI task that investigates the critical neuroanatomy subserving accurate assessment of memory performance to study how this relates to memory self-awareness. Additionally, we plan to use transcranial magnetic stimulation (TMS) to demonstrate that the DMN is causally related to self-assessment of memory performance in our fMRI task. Whether perceived changes in memory in older adults parallel changes in brain pathology indicative of AD is uncertain. The candidate's preliminary work suggests that increased A? deposition (a major histopathological finding in AD) in healthy older adults modifies the association between memory self-appraisal and functional connectivity within the DMN, such that increased subjective memory complaints were related to decreased connectivity between the medial prefrontal cortex and posterior cingulate. To investigate this further, we will use data across the clinical stages of AD (including mild cognitive impairment and mild AD patients) to determine whether impaired memory self-awareness coincides with functional disconnection and increased A? pathology in core regions of the DMN. Furthermore, using longitudinal data of older adults and patients across the clinical stages of AD, we will investigat whether pathophysiological changes in the DMN portend loss in memory self- awareness and anosognosia at follow-up (4 years). The proposed research will leverage a rich multi-modality dataset available from a NIA-funded cohort (Harvard Aging Brain Study) and provides a unique avenue of investigation for the candidate. The findings are expected to have important clinical implications, as improved understanding of anosognosia may lead to interventions that would lessen its impact on wellbeing.

Public Health Relevance

The proposed project uses a multimodal approach to investigate the neural networks underlying memory self- awareness and to elucidate how anosognosia might evolve from pathophysiological changes occurring in these networks. First, we will develop and utilize a novel and unique combination of MR imaging and TMS measures to investigate the neural networks by which normal older adults monitor and estimate their memory abilities. Finally, using PET and MR imaging we will investigate whether dysfunction and biomarker evidence of pathology in these networks portends loss of self-awareness and anosognosia in normal older adults as well as patients across the early clinical stages of AD.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Scientist Development Award - Research & Training (K01)
Project #
Application #
Study Section
Neuroscience of Aging Review Committee (NIA)
Program Officer
Hsiao, John
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Brigham and Women's Hospital
United States
Zip Code
d'Oleire Uquillas, Federico; Jacobs, Heidi I L; Hanseeuw, Bernard et al. (2018) Interactive versus additive relationships between regional cortical thinning and amyloid burden in predicting clinical decline in mild AD and MCI individuals. Neuroimage Clin 17:388-396
Vannini, Patrizia; Amariglio, Rebecca; Hanseeuw, Bernard et al. (2017) Memory self-awareness in the preclinical and prodromal stages of Alzheimer's disease. Neuropsychologia 99:343-349
Buckley, Rachel F; Hanseeuw, Bernard; Schultz, Aaron P et al. (2017) Region-Specific Association of Subjective Cognitive Decline With Tauopathy Independent of Global ?-Amyloid Burden. JAMA Neurol 74:1455-1463
Vannini, Patrizia; Hanseeuw, Bernard; Munro, Catherine E et al. (2017) Anosognosia for memory deficits in mild cognitive impairment: Insight into the neural mechanism using functional and molecular imaging. Neuroimage Clin 15:408-414
Aghjayan, Sarah L; Buckley, Rachel F; Vannini, Patrizia et al. (2017) The influence of demographic factors on subjective cognitive concerns and beta-amyloid. Int Psychogeriatr 29:645-652
Vannini, Patrizia; Hanseeuw, Bernard; Munro, Catherine E et al. (2017) Hippocampal hypometabolism in older adults with memory complaints and increased amyloid burden. Neurology 88:1759-1767
Donovan, Nancy J; Okereke, Olivia I; Vannini, Patrizia et al. (2016) Association of Higher Cortical Amyloid Burden With Loneliness in Cognitively Normal Older Adults. JAMA Psychiatry 73:1230-1237
Amariglio, Rebecca E; Mormino, Elizabeth C; Pietras, Alison C et al. (2015) Subjective cognitive concerns, amyloid-?, and neurodegeneration in clinically normal elderly. Neurology 85:56-62