Arterial stiffening influences neurodegeneration, other 'adverse brain outcomes in aging'

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.”