[R01] Cerebrovascular reactivity as a VCID biomarker in CADASIL
Ente: National Institute on Aging
Scadenza: 2029-06-30
Importo max: 736.257 EUR
Paese: US
Descrizione
PROJECT SUMMARY
CADASIL (Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy) is
the most common monogenic cause of stroke and vascular contributions to cognitive impairment and dementia
(VCID). In this project, we will study CADASIL patients with NOTCH3 mutations. Preclinical studies have
indicated that NOTCH3 mutations are associated with structural and functional changes in the vascular smooth
muscle cells and the loss of pericyte function. Thus, studying CADASIL patients with NOTCH3 mutations is an
ideal approach to investigate early physiological changes associated with VCID in gene mutation carriers, prior
to the onset of clinical symptoms. We will examine cerebrovascular reactivity (CVR), a cerebral small vessel
disease (SVD) functional marker, in a subset of participants from the first North American longitudinal cohort
(CADASIL Consortium). This CADASIL Consortium includes 400 adults with CADASIL NOTCH3 mutations and
100 non-carrier controls. A key feature of CADASIL and other SVD is the early development of white matter
(WM) hyperintensities and these features are often irreversible. Functional declines in microvascular health are
thought to occur earlier in the development of the disease and may underlie the WM changes in CADASIL. CVR
is a sensitive measure of microvascular function and reflects the ability of small vessels to dilate in response to
vasoactive stimuli. Thus, the objective of this application is to determine the impact of NOTCH3 mutations on
CVR, and explore potential associations with clinical, neuropsychological, neuroimaging, and biofluid markers of
VCID. To achieve this, we will leverage participants and data from the longitudinal cohort with NOTCH3 mutation
carriers (CADASIL Consortium) and compare with healthy non-carriers. To enhance feasibility, we will use a
novel, yet validated CVR assessment that uses breath modulation and is suitable for multi-site MRI data
collection in the following specific aims. In Aim 1 we will examine if CVR is lower in NOTCH3 mutation carriers
with varying disease severity (asymptomatic, symptomatic, and symptomatic with functional decline) when
compared with healthy non-carrier controls. In Aim 2 we will determine if CVR in NOTCH3 mutation carriers is
associated with other biomarkers of VCID and CADASIL phenotypic markers. In Aim 3 we will characterize the
trajectory of change in CVR in NOTCH3 mutation carriers and non-carrier controls (over 18 months) and
determine the association with other biomarkers of VCID and CADASIL phenotypic markers. Upon completion,
this application will provide critical information on the pathogenesis of VCID using participants with a SVD
autosomal dominant source, that will expand beyond patients of the rare disease CADASIL. This approach aligns
with recent NIH recommendations emphasizing the need for human studies to identify and confirm biomarkers
of vascular processes related to cognitive impairment. Importantly, t
Istituzione: UNIVERSITY OF WISCONSIN-MADISON
PI: JILL NICOLE BARNES, Hanzhang Lu, Jane S Paulsen
Progetto: 5R01AG085602-03
Settori: National Institute on Aging
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