Central arterial stiffening contributed to biomarker evidence of
neuroinflammation and neurodegeneration in older adults, according to a
community-based observational study published in Neurology.
“As arterial stiffness increases with age, the aorta is less able to buffer pulsatile energy,” Elizabeth E. Moore, BS,
a medical student at the Vanderbilt Memory and Alzheimer’s Center, and
colleagues wrote. “Potentially harmful pressure is thereby transmitted
to the cerebral microcirculation, contributing to microcirculatory
damage, vascular remodeling and subsequently lower cerebral blood flow.”
Moore
and colleagues conducted this study to test a possible association
between increased aortic stiffening and cerebrospinal fluid evidence for
Alzheimer’s disease pathology, neurodegeneration, synaptic disfunction,
neuroaxonal injury and neuroinflammation. Specifically, they looked at
amyloid beta and phosphorylated tau
(p-tau) for AD pathology, total tau for neurodegeneration, neurogranin
for synaptic dysfunction, neurofilament light for neuroaxonal injury and
YKL-40 and soluble TREM2 for neuroinflammation.
The
researchers analyzed pulse wave velocity (PWV) and CSF data from 146
adults aged 60 years and older with no history of stroke or dementia who
participated in the Vanderbilt Memory and Aging Project. The average
age of participants was 72 years; 66% were male and 94% identified as
non-Hispanic white people.
Moore and colleagues conducted
cardiac magnetic resonance to evaluate PWV and lumbar punctures to
obtain CSF. They conducted linear regressions that related aortic PWV to
CSF amyloid beta, p-tau, total tau, neurogranin, neurofilament light,
YKL-40 and soluble TREM2 concentrations. The researchers adjusted for
age, race/ethnicity, education, APOE e4 status, Framingham Stroke
Risk Profile and cognitive diagnosis. They also repeated testing of the
models to assess PWV interactions with age, diagnosis, APOE e4 and hypertension on each biomarker, according to the study results.
Study results
Moore and colleagues found that aortic PWV interacted with age on p-tau (beta = 0.31; P = .04), total tau (beta = 2.67; P = .05), neurogranin (beta = 0.94; P = .04) and soluble TREM2 (beta = 20.4; P = .05). In participants aged older than 73 years, higher aortic PWV correlated with higher p-tau (beta = 2.4; P = .03), total tau (beta = 19.3; P = .05), neurogranin (beta = 8.4; P = .01) and YKL-40 concentrations (beta = 7,880; P = .005). PMW also moderately interacted with diagnosis on neurogranin (beta = 10.76; P = .03) and hypertension on YKL-40 (beta = 18,020; P = .001).
“This
study found [that] associations between increased central arterial
stiffening and increased in vivo molecular biomarker evidence of
neuroinflammation, synaptic dysfunction, phosphorylated tau and
neurodegeneration are uniquely dependent on age and vascular health
status,” Moore and colleagues wrote. “Collectively, these findings offer
new insights into novel pathways underlying connections between
increased arterial stiffness and adverse brain outcomes and confirm prior observations focused on neurodegeneration and amyloidosis outcomes.”
The
study is also one of the first to report correlations between “a gold
standard measurement of central arterial stiffening” and in vivo CSF
biomarkers for neuroinflammatory processes and synaptic dysfunction
among adults aged 73 years and over as well as older adults with
hypertension, according to the researchers.
“Given that an
estimated 72% of older adults are hypertensive and the same molecular
biomarkers were implicated in both [adults aged over 73 years] and
hypertensive participants, results may reflect a complex yet highly
prevalent and overlapping pathway to adverse brain outcomes in aging,”
Moore and colleagues wrote. “Future research using larger samples should
investigate these potentially complex interactions, including whether
these processes are overlapping or separate pathways of injury.”
Related editorial
In a related editorial, Timothy M. Hughes, PhD, assistant professor of gerontology and geriatric medicine at Wake Forest University School of Medicine, and Ihab Hajjar, MD, associate professor of medicine — general medicine and geriatrics at Emory University School of Medicine, discussed
preceding research about vascular cognitive impairment and dementia.
While Hughes and Hajjar recognized that the study by Moore and
colleagues “adds important insights into the previously unexplored
molecular aspects of vascular contributions to AD pathology,
neurodegeneration and neuroinflammation underlying AD pathophysiology,”
several limitations impacted the results, such as the use of cardiac
MRI. The primarily concern with cardiac MRI, according to Hughes and
Hajjar, is its limited temporal resolution, “which compromises its
precision over the short path length” and may not have the ability to
“resolve fast PWVs in individuals with stiff aortas.”
Hughes
and Hajjar also discussed “inconsistencies” highlighted by Moore and
colleagues that should be addressed in future research. This includes an
“unresolved” question of whether it is necessary for age to modify the
correlations between PWV and CSF, which may offer ”a critical window”
for prevention in the future.
“Taken together, this body of
work provides further evidence that arterial stiffness is associated
with multiple aspects of dementia pathophysiology linking [vascular
cognitive impairment and dementias] and [Alzheimer’s disease and related
dementias]. The framework for [Alzheimer’s disease and related
dementias] is adaptable to new evidence; a ‘vascular biomarker group
could be added, that is, ATV(N), when a clear definition of what
constitutes V+ is developed.’ Defining ‘V’ is a critical challenge that
lies ahead,” Hughes and Hajjar wrote. “Certainly, this ’V‘ designation
will derive from a single or index of cerebrovascular biomarkers that
have ’upstream‘ drivers. The work by Moore and colleagues and others
places arterial stiffness in this ’upstream‘ position; therefore, it is
an ideal place for prevention research.”
