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Principal Investigator: Valentina Perosa
Organization: MASSACHUSETTS GENERAL HOSPITAL
Fiscal Year: 2024
Award: $123,714
Funding agency: National Institute on Aging
Project Summary/Abstract
Title: Understanding the mechanistic link between vascular dysfunction and Alzheimer’s disease-related protein
accumulation in the medial temporal lobe.
Cerebral small vessel disease (CSVD), which affects small vessels of the brain in the form of cerebral amyloid
angiopathy (CAA) or arteriolosclerosis, is either primarily responsible or a significantly contributing factor to
Alzheimer’s disease and related dementias (AD/ADRD). However, it remains unclear whether vascular pathology
and AD-related pathology independently contribute to dementia or causally interact with each other. Dysfunction
in perivascular clearance, one of the systems responsible for the disposal of metabolic waste products from the
brain, and blood-brain barrier (BBB) leakage, both occur when CSVD pathology is present and are candidate
mechanisms that could explain this interaction. The objective of the proposed research is to pinpoint the
reciprocal interaction between CSVD and AD-related pathology, in order to infer its underlying
mechanisms. The focus will be on the medial temporal lobe (MTL), a critical brain region for the development
of AD/ADRD, because it is fundamental for cognition and it is a site where a multiplicity of AD-related pathologies
coexist (e.g. Aβ-plaques, neurofibrillary tau tangles, TAR DNA binding protein 43, and neuronal loss), some of
which in very early stages of the disease (e.g. tangles). Firstly, the applicant will investigate whether CSVD in
the MTL worsens AD-related pathology (Hypothesis 1). Secondly, she will infer the contributing role of
perivascular clearance dysfunction and BBB-leakage to these interactions (Hypothesis 2) and aims to create
and validate neuroimaging markers of microvascular health in the MTL (Hypothesis 3). The innovation of this
proposal lies in the use of quantitative neuroimaging and neuropathological methods, including ultra-high
resolution ex vivo MRI, polarization-sensitive optical coherence tomography, and deep-learning based measures
of MRI and serial histology. The proposed investigations address a significant knowledge gap, related to the
complex interactions between AD and CSVD, which has been emphasized as a research priority by the NIH.
Successful completion of the aims will result in histologically validated neuroimaging markers of microvascular
health of the MTL, which can be applied to in vivo studies to understand the impact of disease-modifying
interventions. This proposal leverages the candidate’s existing skillset and demonstrated expertise in vascular
pathology and will provide an invaluable training opportunity to acquire new skills and analytic methods. This
award will be instrumental for a successful transition into an independent investigator. Importantly, the support
of an internationally recognized team of (co-)mentors in human CSVD and AD and the unique resources
available at Massachusetts General Hospital and Harvard Medical School are key ingredients to ensure impactful
results.
Terms: <3-D><3-Dimensional><3D><AD dementia><AD pathology><AD related dementia><ADRD><Abscission><Address><Affect><Alzheimer Type Dementia><Alzheimer disease dementia><Alzheimer sclerosis><Alzheimer syndrome><Alzheimer's><Alzheimer's Disease><Alzheimer's and related dementias><Alzheimer's disease and related dementia><Alzheimer's disease and related disorders><Alzheimer's disease or a related dementia><Alzheimer's disease or a related disorder><Alzheimer's disease or related dementia><Alzheimer's disease pathology><Alzheimer's disease related dementia><Alzheimer's pathology><Alzheimers Dementia><Amentia><Ammon Horn><Amyloid><Amyloid (Aβ) plaques><Amyloid Plaques><Amyloid Substance><Area><Arterioloscleroses><Autopsy><Award><Blood - brain barrier anatomy><Blood Vessels><Blood brain barrier dysfunction><Blood-Brain Barrier><Brain><Brain Nervous System><Brain Vascular Disorders><Brain region><Causality><Cerebral Amyloid Angiopathy><Cerebral small vessel disease><Cerebrovascular Disease><Cerebrovascular Disorders><Clinical><Cognition><Cognitive Disturbance><Cognitive Impairment><Cognitive decline><Cognitive function abnormal><Complex><Congophilic Angiopathy><Contrast Agent><Contrast Drugs><Contrast Media><Cornu Ammonis><Dementia><Development><Disease><Disease Marker><Disorder><Disturbance in cognition><Doppler OCT><Dysfunction><Encephalon><Ensure><Entorhinal Area><Etiology><Excision><Extirpation><Extravasation><Fibrin><Functional disorder><General Hospitals><Goals><Health><Healthcare><Hemato-Encephalic Barrier><Hippocampus><Histologic><Histologically><Histology><Human><Impaired cognition><Impairment><International><Intervention><Intervention Strategies><Intracranial Vascular Diseases><Intracranial Vascular Disorders><Investigation><Investigators><Knowledge><Leakage><Link><MR Imaging><MR Tomography><MRI><MRI biomarker><MRI marker><MRIs><MT-bound tau><Magnetic Resonance Imaging><Maps><Massachusetts><Measures><Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance><Memory><Mentors><Metabolic><Methods><Modern Man><Monitor><Morphology><NIH><NMR Imaging><NMR Tomography><National Institutes of Health><Neuritic Plaques><Neurofibrillary Tangles><Nuclear Magnetic Resonance Imaging><OCT Tomography><Optical Coherence Tomography><Pathologic><Pathology><Pattern><Penetration><Phase><Physiopathology><Predisposition><Primary Senile Degenerative Dementia><Proteins><Radiopaque Media><Removal><Research><Research Personnel><Research Priority><Research Resources><Researchers><Resources><Role><Senile Plaques><Site><Spillage><Surgical Removal><Susceptibility><System><TAR DNA-binding protein 43><TDP-43><TDP43><Training Programs><United States National Institutes of Health><Vascular Diseases><Vascular Disorder><Visualization><Waste Products><Work><Zeugmatography><abnormally aggregated tau protein><amyloid beta plaque><amyloid-b plaque><analytical method><arteriole><aβ plaques><blood vessel disorder><bloodbrain barrier><brain tissue><brain vascular disease><brain vascular dysfunction><burden of disease><burden of illness><causation><cerebral small vessel disorder><cerebral vascular disease><cerebral vascular dysfunction><cerebrovascular amyloidosis><cerebrovascular dysfunction><cognitive dysfunction><cognitive loss><cored plaque><crosslink><deep learning><deep learning method><deep learning strategy><developmental><diffuse plaque><disease burden><disease causation><early biomarkers><early detection biomarkers><early detection markers><entorhinal cortex><filamentous tau inclusion><global health><health care><hippocampal><image-based method><imaging method><imaging modality><in vivo><innovate><innovation><innovative><interventional strategy><intracranial vascular dysfunction><magnetic resonance imaging biomarker><magnetic resonance imaging marker><medial temporal area><medial temporal lobe><medical college><medical schools><mesial temporal area><mesial temporal lobe><microtubule associated protein tau aggregation><microtubule associated protein tau deposit><microtubule bound tau><microtubule-bound tau><necropsy><nerve cell death><nerve cell loss><neural imaging><neuro-imaging><neurofibrillary degeneration><neurofibrillary lesion><neurofibrillary pathology><neuroimaging><neuroimaging biomarker><neuroimaging marker><neurological imaging><neuron cell death><neuron cell loss><neuron death><neuron loss><neuronal cell death><neuronal cell loss><neuronal death><neuronal loss><neuropathologic><neuropathological><neuropathology><novel><optical Doppler tomography><optical coherence Doppler tomography><paired helical filament of tau><pathophysiology><postmortem><primary degenerative dementia><protein TDP-43><protein TDP43><quantitative imaging><resection><school of medicine><self-aggregate tau><senile dementia of the Alzheimer type><skills><social role><spatial relationship><super high resolution><superresolution><tangle><tau><tau PHF><tau Proteins><tau accumulation><tau aggregate><tau aggregation><tau factor><tau fibrillization><tau filament><tau neurofibrillary tangle><tau oligomer><tau paired helical filament><tau polymerization><tau-tau interaction><three dimensional><training opportunity><ultra high resolution><vascular><vascular dysfunction><vasculopathy><τ Proteins><τ aggregation>