Older adults with reduced cerebrovascular reactivity exhibit high white matter hyperintensity burden.

Cerebrovascular reactivity (CVR) deficits may contribute to small vessel disease, such as white matter hyperintensities (WMH). Moreover, apolipoprotein-e4 (APOE4) carriers at genetic risk for Alzheimer's disease exhibit cerebrovascular dysfunction relative to non-carriers. We examined whether older adults, and APOE4 carriers specifically, with diminished CVR would exhibit higher WMH burden. Independently living older adults (N = 125, mean age = 69.2 years; SD = 7.6; 31.2% male) free of dementia or clinical stroke underwent brain MRI to quantify cerebral perfusion during CVR to hypercapnia and hypocapnia and determine WMH volume. Adjusting for age, sex and intracranial volume, hierarchical regression analysis revealed a significant association between whole brain CVR to hypercapnia and WMH overall [B = -.02, 95% CI (-.04, -.008), p =.003] and in APOE4 carriers [B = -.03, 95% CI (-.06, -.009), p =.009]. Findings suggest deficits in cerebral vasodilatory capacity are associated with WMH burden in older adults and future studies are warranted to further delineate the effect of APOE4 on precipitating WMH.

The interactive effect of intra-beat and inter-beat blood pressure variability on neurodegeneration in older adults.

Blood pressure variability (BPV) and arterial stiffness are age-related hemodynamic risk factors for neurodegenerative disease, but it remains unclear whether they exert independent or interactive effects on brain health. When combined with high inter-beat BPV, increased intra-beat BPV indicative of arterial stiffness could convey greater pressure wave fluctuations deeper into the cerebrovasculature, exacerbating neurodegeneration. This interactive effect was studied in older adults using multiple markers of neurodegeneration, including medial temporal lobe (MTL) volume, plasma neurofilament light (NfL) and glial fibrillary acidic protein (GFAP). Older adults (N=105) without major neurological or systemic disease were recruited and underwent brain MRI and continuous BP monitoring to quantify inter-beat BPV through systolic average real variability (ARV) and intra-beat variability through arterial stiffness index (ASI). Plasma NfL and GFAP were assessed. The interactive effect of ARV and ASI on MTL atrophy, plasma NfL, and GFAP was studied using hierarchical linear regression. Voxel-based morphometry (VBM) was used to confirm region-of-interest analysis findings. The interaction between higher ARV and higher ASI was significantly associated with left-sided MTL atrophy in both the region-of-interest and false discovery rate-corrected VBM analysis. The interactive effect was also significantly associated with increased plasma NfL, but not GFAP. The interaction between higher ARV and higher ASI is independently associated with increased neurodegenerative markers, including MTL atrophy and plasma NfL, in independently living older adults. Findings could suggest the increased risk for neurodegeneration associated with higher inter-beat BPV may be compounded by increased intra-beat variability due to arterial stiffness.

Central autonomic network dysfunction and plasma Alzheimer's disease biomarkers in older adults.

BACKGROUND: Higher order regulation of autonomic function is maintained by the coordinated activity of specific cortical and subcortical brain regions, collectively referred to as the central autonomic network (CAN). Autonomic changes are frequently observed in Alzheimer's disease (AD) and dementia, but no studies to date have investigated whether plasma AD biomarkers are associated with CAN functional connectivity changes in at risk older adults. METHODS: Independently living older adults (N = 122) without major neurological or psychiatric disorder were recruited from the community. Participants underwent resting-state brain fMRI and a CAN network derived from a voxel-based meta-analysis was applied for overall, sympathetic, and parasympathetic CAN connectivity using the CONN Functional Toolbox. Sensorimotor network connectivity was studied as a negative control. Plasma levels of amyloid (Aß42, Aß40), neurofilament light chain (NfL), and glial fibrillary acidic protein (GFAP) were assessed using digital immunoassay. The relationship between plasma AD biomarkers and within-network functional connectivity was studied using multiple linear regression adjusted for demographic covariates and Apolipoprotein E (APOE) genotype. Interactive effects with APOE4 carrier status were also assessed. RESULTS: All autonomic networks were positively associated with Aß42/40 ratio and remained so after adjustment for age, sex, and APOE4 carrier status. Overall and parasympathetic networks were negatively associated with GFAP. The relationship between the parasympathetic CAN and GFAP was moderated by APOE4 carrier status, wherein APOE4 carriers with low parasympathetic CAN connectivity displayed the highest plasma GFAP concentrations (B = 910.00, P = .004). Sensorimotor connectivity was not associated with any plasma AD biomarkers, as expected. CONCLUSION: The present study findings suggest that CAN function is associated with plasma AD biomarker levels. Specifically, lower CAN functional connectivity is associated with decreased plasma Aß42/40, indicative of cerebral amyloidosis, and increased plasma GFAP in APOE4 carriers at risk for AD. These findings could suggest higher order autonomic and parasympathetic dysfunction in very early-stage AD, which may have clinical implications.

Beat-to-beat blood pressure variability, hippocampal atrophy, and memory impairment in older adults.

Visit-to-visit blood pressure variability (BPV) predicts age-related hippocampal atrophy, neurodegeneration, and memory decline in older adults. Beat-to-beat BPV may represent a more reliable and efficient tool for prospective risk assessment, but it is unknown whether beat-to-beat BPV is similarly associated with hippocampal neurodegeneration, or with plasma markers of neuroaxonal/neuroglial injury. Independently living older adults without a history of dementia, stroke, or other major neurological disorders were recruited from the community (N = 104; age = 69.5 ± 6.7 (range 55-89); 63% female). Participants underwent continuous blood pressure monitoring, brain MRI, venipuncture, and cognitive testing over two visits. Hippocampal volumes, plasma neurofilament light, and glial fibrillary acidic protein levels were assessed. Beat-to-beat BPV was quantified as systolic blood pressure average real variability during 7-min of supine continuous blood pressure monitoring. The cross-sectional relationship between beat-to-beat BPV and hippocampal volumes, cognitive domain measures, and plasma biomarkers was assessed using multiple linear regression with adjustment for demographic covariates, vascular risk factors, and average systolic blood pressure. Elevated beat-to-beat BPV was associated with decreased left hippocampal volume (P = .008), increased plasma concentration of glial fibrillary acidic protein (P = .006), and decreased memory composite score (P = .02), independent of age, sex, average systolic blood pressure, total intracranial volume, and vascular risk factor burden. In summary, beat-to-beat BPV is independently associated with decreased left hippocampal volume, increased neuroglial injury, and worse memory ability. Findings are consistent with prior studies examining visit-to-visit BPV and suggest beat-to-beat BPV may be a useful marker of hemodynamic brain injury in older adults.

Reliability of beat-to-beat blood pressure variability in older adults.

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. BPV metrics were derived from continuous beat-to-beat blood pressure monitoring data. Two sequential 7-minute 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= .87 and .82 respectively. Additionally, systolic average real variability was the most reliable metric in both the antihypertensive use group, and the no antihypertensive use group. Beat-to-beat dispersion and sequence-based metrics of BPV can be reliably obtained from 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.

Spontaneous cerebrovascular reactivity at rest in older adults with and without mild cognitive impairment and memory deficits.

Background: Older adults with mild cognitive impairment (MCI) exhibit deficits in cerebrovascular reactivity (CVR), suggesting CVR is a biomarker for vascular contributions to MCI. This study examined if spontaneous CVR is associated with MCI and memory impairment. Methods: 161 older adults free of dementia or major neurological/psychiatric disorders were recruited. Participants underwent clinical interviews, cognitive testing, venipuncture for Alzheimer's biomarkers, and brain MRI. Spontaneous CVR was quantified during 5 minutes of rest. Results: Whole brain CVR was negatively associated with age, but not MCI. Lower CVR in the parahippocampal gyrus (PHG) was found in participants with MCI and was linked to worse memory performance on memory tests. Results remained significant after adjusting for Alzheimer's biomarkers and vascular risk factors. Conclusion: Spontaneous CVR deficits in the PHG are observed in older adults with MCI and memory impairment, indicating medial temporal microvascular dysfunction's role in cognitive decline.

Blood pressure variability, central autonomic network dysfunction and cerebral small vessel disease in APOE4 carriers.

Background: Increased blood pressure variability (BPV) is a risk factor for cerebral small vessel disease (CSVD) and neurodegeneration, independent of age and average blood pressure, particularly in apolipoprotein E4 (APOE4) carriers. However, it remains uncertain whether BPV elevation is a cause or a consequence of vascular brain injury, or to what degree injury to the central autonomic network (CAN) may contribute to BPV-associated risk in APOE4 carriers. Methods: Independently living older adults (n=70) with no history of stroke or dementia were recruited from the community and underwent 5 minutes of resting beat-to-beat blood pressure monitoring, genetic testing, and brain MRI. Resting BPV, APOE genotype, CSVD burden on brain MRI, and resting state CAN connectivity by fMRI were analyzed. Causal mediation and moderation analysis evaluated BPV and CAN effects on CSVD in APOE4 carriers (n=37) and non-carriers (n=33). Results: Higher BPV was associated with the presence and extent of CSVD in APOE4 carriers, but not non-carriers, independent of CAN connectivity (B= 18.92, P= .02), and CAN connectivity did not mediate the relationship between BPV and CSVD. In APOE4 carriers, CAN connectivity moderated the relationship between BPV and CSVD, whereby BPV effects on CSVD were greater in those with lower CAN connectivity (B= 36.43, P= .02). Conclusions: Older APOE4 carriers with higher beat-to-beat BPV exhibit more extensive CSVD, independent of average blood pressure, and the strength of CAN connectivity does not mediate these effects. Findings suggest increased BPV is more likely a cause, not a consequence, of CSVD. BPV is more strongly associated with CSVD in APOE4 carriers with lower rsCAN connectivity, suggesting CAN dysfunction and BPV elevation may have synergistic effects on CSVD. Further studies are warranted to understand the interplay between BPV and CAN function in APOE4 carriers.