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Open Access Publications from the University of California

Scholarly Works (8 results)

  • Thesis
  • Peer Reviewed
UC Irvine Electronic Theses and Dissertations (2021)

Background: Cerebral small vessel disease (SVD) is associated with increased risk of stroke and dementia. Progressive and insidious damage to the cerebral microvasculature may also trigger angiogenic processes to promote vessel repair. Elevated circulating endothelial progenitor cell (EPC) levels are observed in response to vascular injury and may represent a vascular protective mechanism. Pro-angiogenic signaling proteins may similarly be elevated with increasing damage to cerebral microvasculature. We aimed to quantify circulating EPCs and examine circulating levels of proangiogenic proteins in older adults with evidence of SVD.

Method: Independently-living older adults (ages 55-90) free of dementia or clinical stroke were recruited from the community and underwent venipuncture and brain MRI. Flow cytometry quantified circulating EPCs as the number of cells in the lymphocyte gate positively expressing EPC surface markers (CD34+CD133+CD309+). Plasma was assayed for proangiogenic factors (VEGF-A, VEGF-C, VEGF-D, Tie-2, Flt-1). Total SVD burden score was determined based on MRI markers, including white matter hyperintensities, cerebral microbleeds and lacunes.

Results: Sixty-four older adults were included. Linear regression revealed that older adults with higher circulating EPC levels exhibited greater total SVD burden (β = 1.0 x 105, 95% CI [0.2, 1.9], p = .019), after accounting for age and sex. Similarly, a positive relationship between circulating VEGF-D and total SVD score was observed, controlling for age and sex (β = .001, 95% CI [0.000, 0.001], p = .048).

Conclusion: These findings suggest that elevated levels of circulating EPCs and VEGF-D correspond with greater cerebral SVD burden in older adults with no history of clinical stroke or dementia. Additional studies are warranted to determine whether activation of systemic angiogenic growth factors and EPCs represents an early attempt to rescue the vascular endothelium and repair damage in cerebral SVD.

    Cover page: Increased Levels of Circulating Angiogenic Cells and Signaling Proteins in Older Adults with Cerebral Small Vessel Disease
    • Article
    • Peer Reviewed
    UC Irvine Previously Published Works (2021)
    The Notch signaling pathway is an evolutionarily conserved cell signaling system known to be involved in vascular development and function. Recent evidence suggests that dysfunctional Notch signaling could play a critical role in the pathophysiology of neurodegenerative diseases. We reviewed current literature on the role of Notch signaling pathway, and specifically Notch receptor genes and proteins, in aging, cerebrovascular disease and Alzheimer's disease. We hypothesize that Notch signaling may represent a key point of overlap between age-related vascular and Alzheimer's pathophysiology contributing to their comorbidity and combined influence on cognitive decline and dementia. Numerous findings from studies of genetics, neuropathology and cell culture models all suggest a link between altered Notch signaling and Alzheimer's pathophysiology. Age-related changes in Notch signaling may also trigger neurovascular dysfunction, contributing to the development of neurodegenerative diseases; however, additional studies are warranted. Future research directly exploring the influence of aberrant Notch signaling in the development of Alzheimer's disease is needed to better understand this mechanism.
      Cover page: Role of Notch signaling in neurovascular aging and Alzheimer’s disease
      • Article
      • Peer Reviewed
      UC Irvine Previously Published Works (2024)
      Blood pressure variability (BPV) is emerging as an important risk factor across numerous disease states, including cerebrovascular and neurodegenerative disease in older adults. However, there is no current consensus regarding specific use cases for the numerous available BPV metrics. There is also little published data supporting the ability to reliably measure BPV across metrics in older adults. The present study derived BPV metrics from continuous beat-to-beat blood pressure monitoring data. Two sequential 7 min waveforms were analyzed. Absolute and relative reliability testing was performed. Differences between antihypertensive medication users and non-users on BPV metric reliability was also assessed. All sequence and dispersion based BPV metrics displayed good test-retest reliability. A measure of BP instability displayed only moderate reliability. Systolic and diastolic average real variability displayed the highest levels of reliability at ICC = 0.87 and 0.82 respectively. Additionally, systolic average real variability was the most reliable metric in both the antihypertensive use group, and the no antihypertensive use group. In conclusion, beat-to-beat dispersion and sequence-based metrics of BPV can be reliably obtained in older adults using noninvasive continuous blood pressure monitoring. Average real variability may be the most reliable and specific beat-to-beat blood pressure variability metric due to its decreased susceptibility to outliers and low frequency blood pressure oscillations.
        Cover page: Reliability of beat-to-beat blood pressure variability in older adults.
        • Article
        • Peer Reviewed
        UC San Francisco Previously Published Works (2022)
        Blood pressure variability is an emerging risk factor for stroke, cognitive impairment, and dementia, possibly through links with cerebral hypoperfusion. Recent evidence suggests visit-to-visit (e.g., over months, years) blood pressure variability is related to cerebral perfusion decline in brain regions vulnerable to Alzheimer's disease. However, less is known about relationships between short-term (e.g., < 24 hours) blood pressure variability and regional cerebral perfusion, and whether these relationships may differ by age. We investigated short-term blood pressure variability and concurrent regional cerebral microvascular perfusion in a sample of community-dwelling older adults without history of dementia or stroke and healthy younger adults. Blood pressure was collected continuously during perfusion MRI. Cerebral blood flow was determined for several brain regions implicated in cerebrovascular dysfunction in Alzheimer's disease. Elevated systolic blood pressure variability was related to lower levels of concurrent cerebral perfusion in medial temporal regions: hippocampus (β = -.60 [95% CI -.90, -.30]; p < .001), parahippocampal gyrus (β = -.57 [95% CI -.89, -.25]; p = .001), entorhinal cortex (β = -.42 [95% CI -.73, -.12]; p = .009), and perirhinal cortex (β = -.37 [95% CI -.72, -.03]; p = .04), and not in other regions, and in older adults only. Findings suggest a possible age-related selective vulnerability of the medial temporal lobes to hypoperfusion in the context of short-term blood pressure fluctuations, independent of average blood pressure, white matter hyperintensities, and gray matter volume, which may underpin the increased risk for dementia associated with elevated BPV.
          Cover page: Selective vulnerability of medial temporal regions to short-term blood pressure variability and cerebral hypoperfusion in older adults
          • Article
          • Peer Reviewed
          UC Irvine Previously Published Works (2022)

          Background

          Perivascular spaces on brain magnetic resonance imaging (MRI) may indicate poor fluid drainage in the brain and have been associated with numerous neurological conditions. Cerebrovascular reactivity (CVR) is a marker of cerebrovascular function and represents the ability of cerebral blood vessels to regulate cerebral blood flow in response to vasodilatory or vasoconstrictive stimuli. We aimed to examine whether pathological widening of the perivascular space in older adults may be associated with deficits in CVR.

          Methods

          Independently living older adults free of dementia or clinical stroke were recruited from the community and underwent brain MRI. Pseudo-continuous arterial spin labeling MRI quantified whole brain cerebral perfusion at rest and during CVR to hypercapnia and hypocapnia induced by visually guided breathing exercises. Perivascular spaces were visually scored using existing scales.

          Results

          Thirty-seven independently living older adults (mean age = 66.3 years; SD = 6.8; age range 55-84 years; 29.7% male) were included in the current analysis. Multiple linear regression analysis revealed a significant negative association between burden of perivascular spaces and global CVR to hypercapnia (B = -2.0, 95% CI (-3.6, -0.4), p = .015), adjusting for age and sex. Perivascular spaces were not related to CVR to hypocapnia.

          Discussion

          Perivascular spaces are associated with deficits in cerebrovascular vasodilatory response, but not vasoconstrictive response. Enlargement of perivascular spaces could contribute to, or be influenced by, deficits in CVR. Additional longitudinal studies are warranted to improve our understanding of the relationship between cerebrovascular function and perivascular space enlargement.
            Cover page: Older adults with perivascular spaces exhibit cerebrovascular reactivity deficitsCreative Commons 'BY-ND' version 4.0 license
            • Article
            • Peer Reviewed
            UC San Francisco Previously Published Works (2022)
            Blood pressure variability is an emerging risk factor for Alzheimer's disease in older adults, independent of average blood pressure levels. Growing evidence suggests increased blood pressure variability is linked to Alzheimer's disease pathophysiology indexed by cerebrospinal fluid and positron emission tomography markers, but relationships with plasma Alzheimer's disease markers have not been investigated. In this cross-sectional study of 54 community-dwelling older adults (aged 55-88, mean age 69.9 [8.2 SD]), elevated blood pressure variability over 5 min was associated with lower levels of plasma Aβ1-42 (standardized ß =  - 0.36 [95% CI - 0.61, - 0.12]; p = 0.005; adjusted R2 = 0.28) and Aβ1-42: Aβ1-40 ratio (ß =  - 0.49 [95% CI - 0.71, - 0.22]; p < 0.001; adjusted R2 = 0.28), and higher levels of total tau (ß = 0.27 [95% CI 0.01, 0.54]; p = 0.04; adjusted R2 = 0.19) and Ptau181:Aβ1-42 ratio (ß = 0.26 [95% CI 0.02, 0.51]; p = 0.04; adjusted R2 = 0.22). Findings suggest higher blood pressure variability is linked to plasma biomarkers of increased Alzheimer's disease pathophysiology.
              Cover page: Blood pressure variability and plasma Alzheimer’s disease biomarkers in older adults
              • Article
              • Peer Reviewed
              UC San Francisco Previously Published Works (2023)

              Background

              Elevated blood pressure (BP) variability is predictive of increased risk for stroke, cerebrovascular disease, and other vascular brain injuries, independent of traditionally studied average BP levels. However, no studies to date have evaluated whether BP variability is related to diminished cerebrovascular reactivity, which may represent an early marker of cerebrovascular dysfunction presaging vascular brain injury.

              Methods

              The present study investigated BP variability and cerebrovascular reactivity in a sample of 41 community-dwelling older adults (mean age 69.6 [SD 8.7] years) without a history of dementia or stroke. Short-term BP variability was determined from BP measurements collected continuously during a 5-minute resting period followed by cerebrovascular reactivity during 5-minute hypocapnia and hypercapnia challenge induced by visually guided breathing conditions. Cerebrovascular reactivity was quantified as percent change in cerebral perfusion by pseudo-continuous arterial spin labeling (pCASL)-MRI per unit change in end-tidal CO2.

              Results

              Elevated systolic BP variability was related to lower whole brain cerebrovascular reactivity during hypocapnia (ß = -0.43 [95% CI -0.73, -0.12]; P = 0.008; adjusted R2 =.11) and hypercapnia (ß = -0.42 [95% CI -0.77, -0.06]; P = 0.02; adjusted R2 = 0.19).

              Conclusions

              Findings add to prior work linking BP variability and cerebrovascular disease burden and suggest BP variability may also be related to prodromal markers of cerebrovascular dysfunction and disease, with potential therapeutic implications.
                Cover page: Older Adults With Higher Blood Pressure Variability Exhibit Cerebrovascular Reactivity Deficits
                • Article
                • Peer Reviewed
                UC Irvine Previously Published Works (2023)
                Dilation of perivascular spaces (PVS) in the brain may indicate poor fluid drainage due to the accumulation of perivascular cell debris, waste, and proteins, including amyloid-beta (Aβ). No prior study has assessed whether plasma Aβ levels are related to PVS in older adults without dementia. Independently living older adults (N = 56, mean age = 68.2 years; Standard deviation (SD) = 6.5; 30.4% male) free of dementia or clinical stroke were recruited from the community and underwent brain MRI and venipuncture. PVS were qualitatively scored and dichotomized to low PVS burden (scores 0-1,) or high PVS burden (score>1). Plasma was assayed using a Quanterix Simoa Kit to quantify Aβ42 and Aβ40 levels. A significant difference was observed in plasma Aβ42/Aβ40 ratio between low and high PVS burden, controlling for age (F[1, 53] = 5.59, p = 0.022, η2 = 0.10), with lower Aβ42/Aβ40 ratio in the high PVS burden group. Dilation of PVS is associated with a lower plasma Aβ42/Aβ40 ratio, which may indicate higher cortical amyloid deposition. Future longitudinal studies examining PVS changes, and the pathogenesis of AD are warranted.
                  Cover page: Enlarged perivascular spaces and plasma Aβ42/Aβ40 ratio in older adults without dementia
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