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BACKGROUND AND OBJECTIVES: Cerebrovascular reactivity (CVR) represents the ability of cerebral blood vessels to regulate blood flow in response to vasoactive stimuli and is related to cognition in cerebrovascular and neurodegenerative conditions. However, few studies have examined CVR in the medial temporal lobe, known to be affected early in Alzheimer disease and to influence memory function. We aimed to examine whether medial temporal CVR is associated with memory function in older adults with and without mild cognitive impairment (MCI). METHODS: In this observational study, independently living older adults free of dementia or stroke were recruited from the community and underwent brain MRI, neuropsychological assessment, and blood draw in an academic research setting. pCASL MRI quantified medial temporal lobe cerebral perfusion during CVR response to hypercapnia. Hypercapnia was induced by visually guided breathing exercises (15 seconds breath holds) during capnographic monitoring. MCI diagnosis and memory performance were assessed through comprehensive neuropsychological assessment. Aβ42/40 and pTau181 levels were quantified in blood plasma. Logistic and hierarchical linear regression examined medial temporal CVR in relation to MCI diagnosis and memory function. RESULTS: In a sample of 144 older adults (mean age = 69.6 years; SD = 7.4%; 34.7% male; mean education = 16.6 years, SD = 2.3), CVR to hypercapnia in the medial temporal lobe was attenuated in individuals with MCI after adjusting for age, sex, education, apolipoprotein ε4 carrier status, Aβ42/40 and pTau181 levels, and vascular risk factors (OR = 0.87, 95% CI [0.77-0.97], p = 0.013). Cerebrovascular reactivity to hypercapnia was associated with verbal memory performance for stories (B = 0.33, 95% CI [0.09-0.57], p = 0.009), a word list (B = 0.10, 95% CI [0.001-0.20], p = 0.048), and visual memory (B = 0.33, 95% CI [0.09-0.57], p = 0.008). DISCUSSION: Deficits in medial temporal CVR are observed in older adults with MCI and are related to worse memory function. Findings suggest that medial temporal cerebrovascular dysfunction is related to cognition and memory before the onset of dementia, independent of changes in Alzheimer pathophysiologic markers. Limitations of the study include the cross-sectional design. Future longitudinal studies are warranted to examine whether early cerebrovascular changes can predict progressive memory decline.

BackgroundBlood pressure variability is increasingly linked with cerebrovascular disease and Alzheimer's disease, independent of mean blood pressure levels. Elevated blood pressure variability is also associated with attenuated cerebrovascular reactivity, which may have implications for functional hyperemia underpinning brain network connectivity. It remains unclear whether blood pressure variability is related to functional network connectivity. We examined relationships between beat-to-beat blood pressure variability and functional connectivity in brain networks vulnerable to aging and Alzheimer's disease.Methods53 community-dwelling older adults (mean [SD] age = 69.9 [7.5] years, 62.3% female) without history of dementia or clinical stroke underwent continuous blood pressure monitoring and resting state fMRI scan. Blood pressure variability was calculated as variability independent of mean. Functional connectivity was determined by resting state fMRI for several brain networks: default, salience, dorsal attention, fronto-parietal, and language. Multiple linear regression examined relationships between short-term blood pressure variability and functional network connectivity.ResultsElevated short-term blood pressure variability was associated with lower functional connectivity in the default network (systolic: standardized ß = -0.30 [95% CI -0.59, -0.01], p = .04). There were no significant associations between blood pressure variability and connectivity in other functional networks or between mean blood pressure and functional connectivity in any network.DiscussionOlder adults with elevated short-term blood pressure variability exhibit lower resting state functional connectivity in the default network. Findings support the role of blood pressure variability in neurovascular dysfunction and Alzheimer's disease. Blood pressure variability may represent an understudied early vascular risk factor for neurovascular dysfunction relevant to Alzheimer's disease, with potential therapeutic implications.

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.

BackgroundElevated 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.MethodsThe 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.ResultsElevated 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).ConclusionsFindings 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.

BackgroundPerivascular 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.MethodsIndependently 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.ResultsThirty-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.DiscussionPerivascular 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.

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.

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

ObjectiveWe previously identified 4 empirically derived mild cognitive impairment (MCI) subtypes via cluster analysis within the Alzheimer's Disease Neuroimaging Initiative (ADNI) and demonstrated high correspondence between patterns of cortical thinning at baseline and each cognitive subtype. We aimed to determine whether our MCI subtypes demonstrate unique longitudinal atrophy patterns.MethodsADNI participants (295 with MCI and 134 cognitively normal [CN]) underwent annual structural MRI and neuropsychological assessments. General linear modeling compared vertex-wise differences in cortical atrophy rates between each MCI subtype and the CN group. Linear mixed models examined trajectories of cortical atrophy over 3 years within lobar regions of interest.ResultsCompared to the CN group, those with amnestic MCI (memory deficit) initially demonstrated greater atrophy rates within medial temporal lobe regions that became more widespread over time. Those with dysnomic/amnestic MCI (naming/memory deficits) showed greater atrophy rates largely localized to temporal lobe regions. The mixed MCI (impairment in all cognitive domains) group showed greater atrophy rates in widespread regions at all time points. The cluster-derived normal group, who had intact neuropsychological performance and normal cortical thickness at baseline despite their MCI diagnosis via conventional diagnostic criteria, continued to show normal cognition and minimal cortical atrophy over 3 years.ConclusionsADNI's purported amnestic MCI sample produced more refined cognitive subtypes with unique longitudinal cortical atrophy rates. These novel MCI subtypes reliably reflect underlying atrophy, reduce false-positive diagnostic errors, and improve prediction of clinical course. Such improvements have implications for the selection of participants for clinical trials and for providing more precise risk assessment for individuals diagnosed with MCI.

PurposeWe used quantitative magnetic resonance imaging to prospectively analyze the association between microstructural damage to memory-associated structures within the medial temporal lobe and longitudinal memory performance after brain radiation therapy (RT).Methods and materialsPatients with a primary brain tumor receiving fractionated brain RT were enrolled on a prospective trial (n = 27). Patients underwent high-resolution volumetric brain magnetic resonance imaging, diffusion-weighted imaging, and neurocognitive testing before and 3, 6, and 12 months post-RT. Medial temporal lobe regions (hippocampus; entorhinal, parahippocampal, and temporal pole white matter [WM]) were autosegmented, quantifying volume and diffusion biomarkers of WM integrity (mean diffusivity [MD]; fractional anisotropy [FA]). Reliable change indices measured changes in verbal (Hopkins Verbal Learning Test-Revised) and visuospatial (Brief Visuospatial Memory Test-Revised [BVMT-R]) memory. Linear mixed-effects models assessed longitudinal associations between imaging parameters and memory.ResultsVisuospatial memory significantly declined at 6 months post-RT (mean reliable change indices, -1.3; P = .012). Concurrent chemotherapy and seizures trended toward a significant association with greater decline in visuospatial memory (P = .053 and P = .054, respectively). Higher mean dose to the left temporal pole WM was significantly associated with decreased FA (r = -0.667; P = .002). Over all time points, smaller right hippocampal volume (P = .021), lower right entorhinal FA (P = .023), greater right entorhinal MD (P = .047), and greater temporal pole MD (BVMT-R total recall, P = .003; BVMT-R delayed recall, P = .042) were associated with worse visuospatial memory. The interaction between right entorhinal MD (BVMT-R total recall, P = .021; BVMT-R delayed recall, P = .004) and temporal pole FA (BVMT-R delayed recall, P = .024) significantly predicted visuospatial memory performance.ConclusionsBrain tumor patients exhibited visuospatial memory decline post-RT. Microstructural damage to critical memory regions, including the hippocampus and medial temporal lobe WM, were associated with post-RT memory decline. The integrity of medial temporal lobe structures is critical to memory performance post-RT, representing possible avoidance targets for memory preservation.

IntroductionThe Alzheimer's Disease Neuroimaging Initiative (ADNI) separates "early" and "late" mild cognitive impairment (MCI) based on a single memory test. We compared ADNI's MCI classifications to our neuropsychological approach, which more broadly assesses cognitive abilities.MethodsThree hundred thirty-six ADNI-2 participants were classified as "early" or "late" MCI. Cluster analysis was performed on neuropsychological test data, and participants were reclassified based on cluster results. These two staging approaches were compared on progression rates, cerebrospinal fluid biomarkers, and cortical thickness profiles.ResultsThere was little correspondence between the two staging methods. ADNI's early MCI group included a large proportion of false-positive diagnostic errors. The reclassified neuropsychological MCI groups showed steeper survival curves and more abnormal biomarkers.ConclusionsOur novel neuropsychological approach improved the staging of MCI by (1) capturing individuals at an early symptomatic stage, (2) minimizing false-positive cases, and (3) identifying a late MCI group further along the disease trajectory.

ObjectivesTemporal lobe epilepsy (TLE) is known to affect large-scale gray and white matter networks, and these network changes likely contribute to the verbal memory impairments observed in many patients. In this study, we investigate multimodal imaging patterns of brain alterations in TLE and evaluate the sensitivity of different imaging measures to verbal memory impairment.MethodsDiffusion tensor imaging (DTI), volumetric magnetic resonance imaging (vMRI), and resting-state functional MRI (rs-fMRI) were evaluated in 46 patients with TLE and 33 healthy controls to measure patterns of microstructural, structural, and functional alterations, respectively. These measurements were obtained within the white matter directly beneath neocortex (ie, superficial white matter [SWM]) for DTI and across neocortex for vMRI and rs-fMRI. The degree to which imaging alterations within left medial temporal lobe/posterior cingulate (LMT/PC) and left lateral temporal regions were associated with verbal memory performance was evaluated.ResultsPatients with left TLE and right TLE both demonstrated pronounced microstructural alterations (ie, decreased fractional anisotropy [FA] and increased mean diffusivity [MD]) spanning the entire frontal and temporolimbic SWM, which were highly lateralized to the ipsilateral hemisphere. Conversely, reductions in cortical thickness in vMRI and alterations in the magnitude of the rs-fMRI response were less pronounced and less lateralized than the microstructural changes. Both stepwise regression and mediation analyses further revealed that FA and MD within SWM in LMT/PC regions were the most robust predictors of verbal memory, and that these associations were independent of left hippocampal volume.SignificanceThese findings suggest that microstructural loss within the SWM is pronounced in patients with TLE, and injury to the SWM within the LMT/PC region plays a critical role in verbal memory impairment.

Background: Cerebrovascular reactivity (CVR) is a marker of cerebrovascular function defined by blood flow changes in response to vasoactive stimuli, which may represent a valuable indicator of risk for vascular brain injury and cognitive decline. Understanding of sex specific CVR patterns is limited, yet likely important for understanding vascular risk. Previous research on sex differences in CVR is mixed, and has predominantly focused on younger adults and utilized Transcranial Doppler ultrasound approaches that focus on large intracranial artery flow. We sought to determine sex differences in CVR responses in older adults using MRI approaches focused on microvascular vasodilatory responses. Method: Independently living older adults, (N = 127, mean age = 69.9 years; SD = 7.27; age range 55‐90 years, 34.6% male, mean education = 16.7 years; SD = 2.2) free of dementia, clinical stroke, and major neurological or psychiatric disorder, were recruited from the community and underwent brain MRI and clinical interview. Pseudo‐continuous arterial spin‐labeling MRI and capnography was used to quantify whole brain cerebral perfusion during CVR to hypercapnia induced by visually guided, 15sec breath‐hold exercises. Sex differences in whole brain CVR to hypercapnia were studied. Result: An independent samples t‐test revealed women (M = 6.52, SD = 5.40) to have significantly higher CVR to hypercapnia than men (M = 4.24, SD = 4.20), t(125) = 2.63, p = 0.01, which remained significant in an ANCOVA model after correcting for age F(125) = 4.407, p = 0.038. Conclusion: Older men exhibited lower cerebral vasodilatory responses to hypercapnia relative to women, independent of the effects of aging. These results are consistent with prior findings suggesting that women have higher cerebral blood flow relative to age‐matched men. Findings could suggest older women are at increased risk of vascular brain injury and resulting cognitive decline, and inform future studies of CVR as a marker of risk in this population. [ABSTRACT FROM AUTHOR]

Background: Optimal cerebral blood flow is crucial to maintaining cognitive function. Cerebrovascular reactivity (CVR) is a dynamic measure of cerebrovascular function which represents the ability of cerebral blood vessels to regulate blood flow in response to vasoactive stimuli. Prior studies have demonstrated an association between impaired CVR and cognitive function in cerebrovascular and neurodegenerative conditions, including cerebral amyloid angiopathy and Alzheimer disease. However, few studies have examined the association between cerebrovascular reactivity and cognitive function in older adults prior to the onset of cognitive decline. Method: Independently living older adults (N = 111, mean age = 69.2 years; SD = 7.1; age range 55‐89 years; 29.7% male, mean education = 16.5 years; SD = 2.4) free of dementia or clinical stroke were recruited from the community and underwent brain MRI and neuropsychological assessment. Pseudo‐continuous arterial spin labeling MRI quantified whole brain cerebral perfusion during CVR to hypercapnia (vasodilation) induced by visually guided breathing exercises (15s breath holds) and indexed by capnography. We specifically examined verbal and visual memory, assessed using the RAVLT word list learning and memory, WMS‐R Logical Memory I and II, and WMS‐IV Visual Reproduction I and II. Result: Adjusting for age, sex and education, multiple regression analyses revealed a significant positive association between CVR to hypercapnia and RAVLT word list delayed recall (B =.084, 95% CI (.001,.167), p =.048), Logical Memory II (B =.240, 95% CI (.012,.468), p =.039) and Visual Reproduction II (B =.280, 95% CI (.097,.464), p =.003). Conclusion: In older adults without stroke or dementia, higher cerebrovascular reactivity is associated with better memory function. Cerebrovascular dysfunction is known to precede and contribute to the development of cognitive impairment. These findings suggest that cerebrovascular dysfunction influences cognitive performance even in preclinical stages. Future longitudinal may elucidate whether early cerebrovascular reactivity changes can predict long‐term development of dementia. [ABSTRACT FROM AUTHOR]

Background: APOE4 carriers exhibit cerebrovascular dysfunction which may contribute to the development of cognitive decline and dementia; however, the mechanisms underlying this pathophysiology remain unknown. Impaired cerebrovascular reactivity (CVR) may be associated with vascular injury, inflammation, and endothelial dysfunction. To examine whether these processes may be involved in CVR deficits in APOE4 carriers, we explored whether plasma levels of vascular injury markers indicative of inflammation and endothelial dysfunction are associated with impaired CVR to hypercapnia and hypocapnia in older APOE4 carriers. Method: Sixty‐five independently living older adults (mean age = 69.3 years; SD = 8.6; age range 55‐89 years; 30.8% male) free of dementia or clinical stroke were recruited from the community and underwent venipuncture and brain MRI. Plasma was assayed for vascular injury markers (Serum amyloid A (SAA), C‐reactive protein (CRP), intercellular adhesion molecule 1 (ICAM‐1), vascular cell adhesion molecule 1 (VCAM‐1)) and values were log‐transformed. APOE genotyping was conducted on blood samples. Pseudo‐continuous arterial spin labeling MRI quantified whole brain cerebral perfusion during CVR to hypocapnia (0.1Hz paced breathing; vasoconstriction). Result: Adjusting for age and sex, multiple linear regression analysis revealed a significant association between whole brain CVR to hypocapnia and circulating levels of SAA, VCAM‐1 and ICAM‐1. Analyses stratified by APOE4 status revealed a significant association between whole brain CVR to hypocapnia and levels of SAA [B = ‐5.39, 95% CI (‐9.78, ‐1.01), p =.018], VCAM‐1 [B = ‐10.70, 95% CI (‐17.59, ‐3.82), p =.004] and ICAM‐1 [B = ‐10.95, 95% CI (‐17.44, ‐4.46), p =.002] in APOE4 carriers but not non‐carriers. Conclusion: Findings suggest that elevated levels of vascular injury markers are associated with deficits in cerebral vasoconstriction, particularly in APOE4 carriers at genetic risk for Alzheimer's disease. SAA, VCAM‐1 and ICAM‐1 are known to be involved in inflammation and endothelial dysfunction, and elevated levels are associated with cerebrovascular resistance and cognitive impairment. Our findings suggest that APOE4 carriers may be particularly vulnerable to these pathophysiological processes. Further longitudinal studies may elucidate whether inflammation and endothelial dysfunction precede or precipitate CVR deficits and contribute to cognitive decline in APOE4 carriers. [ABSTRACT FROM AUTHOR]

Background: Depletion of blood-derived progenitor cells, including so called "early endothelial progenitor cells", has been observed in individuals with early stage Alzheimer's disease relative to matched older control subjects. These findings could implicate the loss of angiogenic support from hematopoietic progenitors or endothelial progenitors in cognitive dysfunction. Objective: To investigate links between progenitor cell proliferation and mild levels of cognitive dysfunction. Methods: We conducted in vitro studies of blood-derived progenitor cells using blood samples from sixty-five older adults who were free of stroke or dementia. Peripheral blood mononuclear cells from venous blood samples were cultured in CFU-Hill media and the number of colony forming units were counted after 5 days in vitro. Neuropsychological testing was administered to all participants. Results: Fewer colony forming units were observed in samples from older adults with a Clinical Dementia Rating global score of 0.5 versus 0. Older adults whose samples developed fewer colony forming units exhibited worse performance on neuropsychological measures of memory, executive functioning, and language ability. Conclusion: These data suggest blood progenitors may represent a vascular resilience marker related to cognitive dysfunction in older adults. [ABSTRACT FROM AUTHOR]

Background: Cerebral small vessel disease (SVD) is associated with increased risk of stroke and dementia. Progressive damage to the cerebral microvasculature may also trigger angiogenic processes to promote vessel repair. Elevated levels of circulating endothelial progenitor cells (EPCs) and pro-angiogenic signaling proteins are observed in response to vascular injury. We aimed to examine circulating levels of EPCs and proangiogenic proteins in older adults with evidence of SVD. Methods: Older adults (ages 55–90) free of dementia or stroke underwent venipuncture and brain magnetic resonance imaging (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, and 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 × 105, 95% CI (0.2, 1.9), p = 0.019], 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 = 0.001, 95% CI (0.000, 0.001), p = 0.048]. Conclusion: These findings suggest that elevated levels of circulating EPCs and VEGF-D correspond with greater cerebral SVD burden in older adults. 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 SVD. [ABSTRACT FROM AUTHOR]

Background: The locus coeruleus (LC) innervates the cerebrovasculature and plays a critical role in optimally regulating cerebral blood flow. However, few studies have examined potential relationships between these systems in humans with widely available neuroimaging methods, and none have explored how relationships may change in the presence of growing Alzheimer's disease (AD) pathology. Method: Participants were 66 community‐dwelling older adults free of dementia (ages 55‐87) recruited at the University of Southern California. Pseudocontinuous arterial spin labeling (pCASL) MRI measured regional perfusion, and T1‐fast spin echo (T1‐FSE) MRI quantified rostral LC contrast, a well‐established measure of LC structural integrity. Subsets of participants underwent neuropsychological testing (n = 36) as well as fasting venipuncture to measure plasma AD biomarker concentrations of Aβ42/40 ratio (n = 56) and ptau181 (n = 35). Multiple linear regression models examined associations among regional perfusion, LC integrity, and cognition (episodic memory, attention, executive function). Moderation analyses included additional terms for plasma AD biomarker concentrations and plasma x LC interaction effects. Result: Higher LC‐MRI contrast was linked to higher frontal (medial and lateral orbitofrontal) perfusion but lower limbic (amygdala and entorhinal) perfusion. Greater LC‐MRI contrast was also associated with better episodic memory recall and recognition but not measures of attention or executive function. Plasma Aβ42/40 ratio and ptau181 moderated LC‐perfusion relationships such that associations significantly weakened in the presence of greater pathology. Conclusion: This is the first human study to directly investigate associations between LC integrity and perfusion in a well‐characterized sample with neuroimaging, cognitive, and AD biomarker data. LC integrity tracked episodic memory performance along with cerebral perfusion, while greater AD pathology in preclinical populations disrupted LC‐perfusion relationships, suggesting that growing amyloid and tau pathology may negatively impact the LC's ability to optimally regulate cerebral blood flow. Taken together, our findings highlight the importance of tracking the LC over the AD disease course. Concurrent multimodal imaging of the LC and cerebrovascular function may have potential as a novel non‐invasive biomarker, and future studies should track its utility longitudinally and its relationship with disease severity and other disease markers (e.g., grey matter atrophy, amyloid/tau PET). [ABSTRACT FROM AUTHOR]

Background: Blood pressure variability is an emerging risk indicator for cerebrovascular disease and Alzheimer's disease, independent of traditionally studied mean blood pressure levels. Recent studies suggest elevated blood pressure variability in older adults is also associated with attenuated cerebrovascular reactivity, which may have implications for functional hyperemia underpinning brain network connectivity. However, it remains unclear whether blood pressure variability is related to functional network connectivity. We examined relationships between beat‐to‐beat blood pressure variability in older adults and functional connectivity in multiple brain networks vulnerable to Alzheimer's disease and related disorders (AD/ADRD). Method: 32 community‐dwelling older adults (mean [SD] age = 69.6 [7.5] years) without history of dementia or clinical stroke underwent continuous blood pressure monitoring during a 5‐minute period of rest and resting state fMRI. Blood pressure variability was calculated as variability independent of mean, an increasingly used index of variability uncorrelated with mean blood pressure levels. Functional connectivity was determined by resting state fMRI for several brain networks: default mode, salience, dorsal attention, fronto‐parietal, and language. Multiple linear regression examined relationships between blood pressure variability and functional network connectivity, controlling for age, sex, and mean blood pressure. Associations with mean blood pressure were also explored to directly compare potential effects with blood pressure variability. Result: Elevated blood pressure variability was associated with lower functional connectivity in the default mode network (ß = ‐.55 [‐1.02, ‐.08]; p =.02). There were no significant associations between blood pressure variability and connectivity in other functional networks (p's =.10 ‐.62). Mean blood pressure was not related to functional connectivity in any network (p's =.08 ‐.98). Conclusion: Older adults with elevated blood pressure variability exhibit resting state functional connectivity deficits in the default mode network. Findings add to literature supporting the role of blood pressure variability in neurovascular dysfunction and AD/ADRD. Blood pressure variability may represent an important but understudied early vascular risk factor for neurovascular dysfunction relevant to AD/ADRD, with potential therapeutic implications. [ABSTRACT FROM AUTHOR]

Objective: Aggregation of phosphorylated tau (pTau) is a hallmark feature of Alzheimer's disease (AD). Novel assays now allow pTau to be measured in plasma. Elevated plasma pTau predicts subsequent development of AD, cortical atrophy and AD-related pathologies in the brain. We aimed to determine whether elevated pTau is associated with cognitive functioning in older adults prior to the development of dementia. Participants and Methods: Independently living older adults (N = 48, mean age = 70.0 years; SD = 7.7; age range 55-88 years; 35.4% male) free of dementia or clinical stroke were recruited from the community and underwent blood draw and neuropsychological assessment. Plasma was assayed using the Quanterix Simoa® pTau-181 V2 Advantage Kit to quantify pTau-181 levels and APOE genotyping was conducted on the blood cell pellet fraction obtained from plasma separation. Global cognition was assessed using the Dementia Rating Scale-2 (DRS-2) and executive function was assessed using the Stroop, D-KEFS-2 Fluency, and Trails Making Test. Diagnosis of mild cognitive impairment (MCI) was determined based on overall neuropsychological performance. Participants were diagnosed as MCI if they scored >1 SD below norm-referenced values on 2 or more tests within a domain (language, executive, memory) or on 3 tests across domains. Results: Multiple linear regression analysis revealed a significant negative association between plasma pTau-181 levels and DRS-2 (B = -2.57, 95% CI (-3.68, -1.47), p <.001), Stroop Color-Word score (B = -2.64, 95% CI (-4.56, - 0.71), p =.009) and Fruits and Vegetables Fluency (B = -1.67, 95% CI (-2.84, -0.49), p =.007), adjusting for age, sex, education and APOE4 status. MCI diagnosis was determined for 43 participants, of which 8 (18.6%) met criteria. Logistic regression analysis revealed that pTau-181 levels are associated with increased odds of MCI diagnosis (OR = 2.18, 95% CI (1.01, 4.68), p =.046), after accounting for age, sex, education and APOE4 status. Conclusions: Elevated plasma pTau-181 is associated with worse cognition, particularly executive function, and predicts MCI diagnosis in older adults. Higher plasma pTau-181 was associated with increased odds of MCI diagnosis. Detection of pTau-181 in plasma allows a novel, non-invasive method to detect burden of one form of AD pathology. These findings lend support to the use of plasma pTau-181 as a valuable marker in detecting even early cognitive changes prior to the development of AD. Additional longitudinal studies are warranted to explore the prognostic value of plasma pTau-181 over time. [ABSTRACT FROM AUTHOR]

Objective: The locus coeruleus (LC) innervates the cerebrovasculature and plays a crucial role in optimal regulation of cerebral blood flow. However, no human studies to date have examined links between these systems with widely available neuroimaging methods. We quantified associations between LC structural integrity and regional cortical perfusion and probed whether varying levels of plasma Alzheimer's disease (AD) biomarkers (Aß42/40 ratio and ptau181) moderated these relationships. Participants and Methods: 64 dementia-free community-dwelling older adults (ages 55-87) recruited across two studies underwent structural and functional neuroimaging on the same MRI scanner. 3D-pCASL MRI measured regional cerebral blood flow in limbic and frontal cortical regions, while T1-FSE MRI quantified rostral LC-MRI contrast, a well-established proxy measure of LC structural integrity. A subset of participants underwent fasting blood draw to measure plasma AD biomarker concentrations (Aß42/40 ratio and ptau181). Multiple linear regression models examined associations between perfusion and LC integrity, with rostral LC-MRI contrast as predictor, regional CBF as outcome, and age and study as covariates. Moderation analyses included additional terms for plasma AD biomarker concentration and plasma x LC interaction. Results: Greater rostral LC-MRI contrast was linked to lower regional perfusion in limbic regions, such as the amygdala (ß = -0.25, p = 0.049) and entorhinal cortex (ß = -0.20, p = 0.042), but was linked to higher regional perfusion in frontal cortical regions, such as the lateral (ß = 0.28, p = 0.003) and medial (ß = 0.24, p = 0.05) orbitofrontal (OFC) cortices. Plasma amyloid levels moderated the relationship between rostral LC and amygdala CBF (Aß42/40 ratio x rostral LC interaction term ß = -0.31, p = 0.021), such that as plasma Aß42/40 ratio decreased (i.e., greater pathology), the strength of the negative relationship between rostral LC integrity and amygdala perfusion decreased. Plasma ptau181levels moderated the relationship between rostral LC and entorhinal CBF (ptau181 x rostral LC interaction term ß = 0.64, p = 0.001), such that as ptau181 increased (i.e., greater pathology), the strength of the negative relationship between rostral LC integrity and entorhinal perfusion decreased. For frontal cortical regions, ptau181 levels moderated the relationship between rostral LC and lateral OFC perfusion (ptau181 x rostral LC interaction term ß = -0.54, p =.004), as well as between rostral LC and medial OFC perfusion (ptau181 x rostral LC interaction term ß = -0.53, p =.005), such that as ptau181 increased (i.e., greater pathology), the strength of the positive relationship between rostral LC integrity and frontal perfusion decreased. Conclusions: LC integrity is linked to regional cortical perfusion in non-demented older adults, and these relationships are moderated by plasma AD biomarker concentrations. Variable directionality of the associations between the LC and frontal versus limbic perfusion, as well as the differential moderating effects of plasma AD biomarkers, may signify a compensatory mechanism and a shifting pattern of hyperemia in the presence of aggregating AD pathology. Linking LC integrity and cerebrovascular regulation may represent an important understudied pathway of dementia risk and may help to bridge competing theories of dementia progression in preclinical AD studies. [ABSTRACT FROM AUTHOR]

Objective: Blood pressure variability (BPV), independent of traditionally targeted average blood pressure levels, is an emerging vascular risk factor for stroke, cerebrovascular disease, and dementia, possibly through links with vascular-endothelial injury. Recent evidence suggests visit-to-visit (e.g., over months, years) BPV is associated with cerebrovascular disease severity, but less is known about relationships with short-term (e.g., < 24 hours) fluctuations in blood pressure. Additionally, it is unclear how BPV may be related to angiogenic growth factors that play a role in cerebral arterial health. Participants and Methods: We investigated relationships between short-term BPV, white matter hyperintensities on MRI, and levels of plasma vascular endothelial growth factor (VEGF) in a sample of community-dwelling older adults (n = 57, ages 55-88) without history of dementia or stroke. Blood pressure was collected continuously during a 5-minute resting period. BPV was calculated as variability independent of mean, a commonly used index of BPV uncorrelated with average blood pressure levels. Participants underwent T2-FLAIR MRI to determine severity of white matter lesion burden. Severity of lesions was classified as Fazekas scores (0-3). Participants also underwent venipuncture to determine levels of plasma VEGF. Ordinal logistic regression examined the association between BPV and Fazekas scores. Multiple linear regression explored relationships between BPV and VEGF. Models controlled for age, sex, and average blood pressure. Results: Elevated BPV was related to greater white matter lesion burden (i.e., Fazekas score) (systolic: OR = 1.17 [95% CI 1.01, 1.37]; p =.04; diastolic: OR = 2.47 [95% CI 1.09, 5.90]; p =.03) and increased levels of plasma VEGF (systolic: ß =.39 [95% CI.11,.67]; adjusted R2 =.16; p =.007; diastolic: ß =.48 [95% CI.18,.78]; adjusted R2 =.18; p =.003). Conclusions: Findings suggest short-term BPV may be related to cerebrovascular disease burden and angiogenic growth factors relevant to cerebral arterial health, independent of average blood pressure. Understanding the role of BPV in cerebrovascular disease and vascular-endothelial health may help elucidate the increased risk for stroke and dementia associated with elevated BPV. [ABSTRACT FROM AUTHOR]

Background: Perivascular spaces (PVS) are fluid‐filled spaces surrounding arterioles, capillaries and venules in the brain, which support metabolic waste clearance. Enlarged PVS are associated with increased dementia risk. Changes in arterial pulsatility are hypothesized to be associated with accumulation of toxic solutes and PVS widening. However, few prior studies have examined whether cerebral blood flow (CBF) is linked to PVS. Method: Independently living older adults (N = 60, mean age = 68.1 years; SD = 7.5; age range 55‐88 years; 30.0% male) free of dementia or clinical stroke were recruited from the community and underwent brain MRI and venipuncture. Pseudo‐continuous arterial spin labeling was utilized to determine CBF in gray matter CBF (mL/100g tissue/min). Regional mean values were determined for regions of interest. PVS were qualitatively scored in the basal ganglia (BG), and centrum semiovale (CS). APOE genotyping was conducted on the blood cell pellet fraction. Result: After accounting for age and sex, multiple linear regression analysis revealed a significant negative association between BG‐PVS and CBF in the left inferior occipital gyrus (B = ‐.07, 95% CI (‐.13, ‐.01), p =.022), right inferior occipital gyrus (B = ‐.06, 95% CI (‐.12, ‐.001), p =.048), left middle occipital gyrus (B = ‐.05, 95% CI (‐.10, ‐.001), p =.047), right middle occipital gyrus (B = ‐.08, 95% CI (‐.13, ‐.02), p =.007), and right inferior temporal gyrus (B = ‐.05, 95% CI (‐.09, ‐.01), p =.025) as well as a positive association in the left precuneus (B =.05, 95% CI (.01,.08), p =.022). When stratified by APOE4 status, all associations were significant only in APOE4 carriers. CS‐PVS were not associated with CBF. Conclusion: These findings indicate altered CBF in older adults with BG‐PVS but not CS‐PVS. Resting CBF was altered in specific brain regions, predominantly in APOE4 carriers. APOE4 is known to convey both vascular risk and risk for Alzheimer's disease (AD). Additional longitudinal studies are warranted to explore the association between PVS and CBF in individuals at risk for dementia to further understand vascular contributions to the development of AD and other dementias. [ABSTRACT FROM AUTHOR]

Summary: Objective: Bilingual healthy adults have been shown to exhibit an advantage in executive functioning (EF) that is associated with microstructural changes in white matter (WM) networks. Patients with temporal lobe epilepsy (TLE) often show EF deficits that are associated with WM compromise. In this study, we investigate whether bilingualism can increase cognitive reserve and/or brain reserve in bilingual patients with TLE, mitigating EF impairment and WM compromise. Methods: Diffusion tensor imaging was obtained in 19 bilingual and 26 monolingual patients with TLE, 12 bilingual healthy controls (HC), and 21 monolingual HC. Fractional anisotropy (FA) and mean diffusivity (MD) were calculated for the uncinate fasciculus (Unc) and cingulum (Cing), superior frontostriatal tract (SFS), and inferior frontostriatal tract (IFS). Measures of EF included Trail Making Test‐B (TMT‐B) and Delis‐Kaplan Executive Function System Color‐Word Inhibition/Switching. Analyses of covariance were conducted to compare FA and MD of the Unc, Cing, SFS, and IFS and EF performance across groups. Results: In bilingual patients, FA was lower in the ipsilateral Cing and Unc compared to all other groups. For both patient groups, MD of the ipsilateral Unc was higher relative to HC. Despite more pronounced reductions in WM integrity, bilingual patients performed similarly to monolingual TLE and both HC groups on EF measures. By contrast, monolingual patients performed worse than HC on TMT‐B. In addition, differences in group means between bilingual and monolingual patients on TMT‐B approached significance when controlling for the extent of WM damage (P = .071; d = 0.62), suggesting a tendency toward higher performance for bilingual patients. Significance: Despite poorer integrity of regional frontal lobe WM, bilingual patients performed similarly to monolingual patients and HC on EF measures. These findings align with studies suggesting that bilingualism may provide a protective factor for individuals with neurological disease, potentially through reorganization of EF networks that promote greater cognitive reserve. [ABSTRACT FROM AUTHOR]

Background: White matter integrity (WMI) may contribute to brain and cognitive reserve in the face of cerebrovascular disease. We investigated WMI in the genu of the corpus callosum (GCC), an area associated with age‐related WMI and cerebrovascular health, and whether it moderates the relationship between WMH and executive functioning in older adults. Method: Participants were dementia‐free older adults (N = 175; age range 55‐89 years, M = 72.78; SD = 0.52; 52% male) from the Alzheimer's Disease Neuroimaging Initiative. Diffusion weighted imaging, T1, and FLAIR scans were used to calculate diffusion tensor imaging (DTI) measures (fractional anisotropy; FA and mean diffusivity; MD) and WMH. Participants were divided into high and low GCC integrity using a median split, stratified by hemisphere and measure (i.e., Right/Left; FA/MD) Neuropsychological tests included Trail Making Test B (TMT B) and Animals. Multiple linear regression determined moderating effects of GCC WMI on WMH and executive function. Education, age, and sex were included as covariates. Result: In individuals with low GCC WMI, WMH correlated with TMT B (Right FA: p = 0.004, R2=.215; Left FA: p =.014, R2=.222; Right MD: p =.009, R2 =.122 ; Left MD: p =.018, R2=.216) and Animals (Right FA: p =.005; Left FA: p =.022; R2=.131; Right MD: p =.054 (trended); R2=.049). In contrast, WMH did not correlate with TMT B (Right FA: p =.219; Right MD: p =.064; Left MD: p =.095) or Animals (Right FA: p =.411; Left FA: p =.280; Right MD: p =.124; Left MD: p =.274) in older adults with high GCC WMI. Conclusion: We observed a differential effect of GCC WMI on the relationship between WMH and executive function, such that greater WMH predicted lower executive functioning only in individuals with low GCC WMI. No relationship between WMH and executive function was found in individuals with high GCC WMI. GCC WMI may thus be a source of cerebrovascular‐related brain reserve and contribute to cognitive resilience by mitigating the clinical consequences of WMH in individuals with cerebrovascular disease. [ABSTRACT FROM AUTHOR]

Background: Cerebrovascular dysfunction occurs with advancing age and is known to contribute to cognitive decline and dementia. Cerebrovascular reactivity is a marker of cerebrovascular function and represents the ability of cerebral blood vessels to regulate cerebral blood flow (CBF) in response to vasodilatory or vasoconstrictive stimuli. Deficits in CVR may contribute to vascular injury and cognitive impairment, however the mechanisms underlying this pathophysiology remain unknown. To explore whether inflammation and endothelial dysfunction may be involved in CVR deficits, we examined whether plasma levels of vascular injury markers indicative of such processes are associated with CVR deficits in older adults. Method: Twenty‐five independently living older adults (mean age = 69.9 years; SD = 8.5; age range 55‐87 years; 24.0% male) free of dementia or clinical stroke were recruited from the community and underwent venipuncture and brain MRI. Plasma was assayed for vascular injury markers (Serum amyloid A (SAA), C‐reactive protein (CRP), intercellular adhesion molecule 1 (ICAM‐1), vascular cell adhesion molecule 1 (VCAM‐1)). Visually guided breath control exercises during pseudo‐continuous arterial spin labeling MRI were utilized to determine global (whole brain) CVR to hypocapnia (0.1Hz paced breathing; vasoconstriction) and hypercapnia (15s breath holds, vasodilation). Pearson correlation and multiple linear regression examined the relationship between circulating vascular injury markers and CVR to hypocapnia and hypercapnia. Result: A significant negative association was observed between circulating levels of SAA and global CVR to hypocapnia (r = ‐.526, p =.017) as well as VCAM‐1 and CVR to hypocapnia (r = ‐.593, p = 0.007). These associations remained significant even after accounting for age and sex in multiple regression analyses. Conclusion: Both SAA and VCAM‐1 are vascular injury markers known to be involved in inflammation and were found to be elevated in older adults with lower global CVR to hypocapnia. Inflammation is associated with atherosclerosis and can lead to endothelial dysfunction, which may ultimately contribute to cognitive decline. Our findings suggest that these biological processes may be related to CVR deficits. Whether higher levels of vascular injury markers represent a protective mechanism or indicate pathological processes remains unknown. [ABSTRACT FROM AUTHOR]

Background: The primary genetic risk factor for Alzheimer’s disease is the apolipoprotein ε4 (APOE‐ε4) allele, which confers significant risk for early symptom onset and future dementia. Prior studies have examined links between memory function and medial temporal perfusion in APOE‐ε4 carriers and non‐carriers, but findings have been mixed regarding the direction of relationships. Additionally, prior work has not examined whether other cognitive domains, such as executive function, are similarly associated with functionally relevant regional perfusion (i.e., in frontal regions). The present study aimed to 1) clarify the relationship between medial temporal perfusion and memory performance and 2) examine novel links between executive function and frontal perfusion in APOE‐ε4 carriers and non‐carriers. Method: Dementia‐free older adults recruited from the community were classified as APOE‐ε4 carriers (n=18) or non‐carriers (n=30) via genotype analysis. We used pseudocontinuous arterial spin labeling MRI to quantify cerebral perfusion in regions involved in memory (medial temporal) and executive function (medial frontal). Comprehensive neuropsychological testing assessed memory (Logical Memory I & II; Visual Reproduction I & II) and executive function (Stroop color‐word interference; Trail making tests A & B, category fluency). Multiple linear regression, modeled separately within carriers and non‐carriers, examined associations between perfusion and cognition, with age, sex, and education as covariates. Result: Within APOE‐ε4 carriers, medial temporal hypoperfusion was associated with worse immediate and delayed recall memory in verbal and visual paradigms. Similarly, frontal hypoperfusion was associated with worse verbal category fluency. In non‐carriers, relationships between medial temporal perfusion and memory were absent. Relationships between frontal perfusion and executive function were in the opposite direction as those observed in APOE‐ε4 carriers, with frontal hyperperfusion predicting worse Stroop color‐word, Trails A, and Trails B performance. Conclusion: We observed positive associations between regional perfusion and corresponding cognitive domains in APOE‐ε4 carriers, while relationships were absent or negative within non‐carriers. Our findings highlight the importance of examining preclinical cerebrovascular dysfunction in relation to cognition in individuals at risk for progression to dementia. Future longitudinal studies will be needed to further examine the value of perfusion, cognition, and APOE‐ε4 carrier status in predicting future decline. [ABSTRACT FROM AUTHOR]

Fear conditioning is considered an animal model of post-traumatic stress disorder. Such models have shown fear conditioning disrupts subsequent rapid eye movement sleep (REM). Here, we provide a translation of these models into humans. Using the fear potentiated startle (FPS) procedure, we examined the effects of fear conditioning and safety signal learning on subsequent REM sleep in healthy adults. We also examined the effects of changes in REM sleep on retention of fear and safety learning. Participants (n = 42 normal controls) spent 3 consecutive nights in the laboratory. The first was an adaptation night. Following the second night, we administered a FPS procedure that included pairing a wrist shock with a threat signal and a safety signal never paired with a shock. The next day, we administered the FPS procedure again, with no wrist shocks to any stimulus, to measure retention of fear and safety. Canonical correlations assessed the relationship between FPS response and REM sleep. Results demonstrated that increased safety signal learning during the initial acquisition phase was associated with increased REM sleep consolidation that night, with 28.4% of the variance in increased REM sleep consolidation from baseline accounted for by safety signal learning. Overnight REM sleep was, in turn, related to overnight retention of fear and safety learning, with 22.5% of the variance in startle retention accounted for by REM sleep. These data suggest that sleep difficulties, specifically REM sleep fragmentation, may play a mechanistic role in post-traumatic stress disorder via an influence on safety signal learning and/or threat-safety discrimination. [ABSTRACT FROM AUTHOR]

Background: Cerebrovascular contributions to aging and cognitive decline have been increasingly recognized, yet the impact of changes in dynamic cerebrovascular function remain unclear. Breath holding and hyperventilation elicit alterations in end‐tidal carbon dioxide (etCO2) and cerebrovascular functions underlying cerebral blood flow (CBF). Manipulation of breathing during neuroimaging may therefore enable assessment of dynamic cerebrovascular changes implicated in cognitive decline. Method: Community‐dwelling younger (n=15) and older (n=40) adults performed guided 15‐second breath holds to induce hypercapnia and paced breathing (alternating between 5‐second inhalation and exhalation) to induce hypocapnia, while undergoing pseudo‐continuous arterial spin labelling (pCASL) MRI. Continuous blood pressure and end‐tidal carbon dioxide (etCO2) were simultaneously collected. Cerebrovascular resistance index (CVRi), was estimated by dividing mean arterial blood pressure by pCASL‐derived CBF. Carbon dioxide reactivity (CO2R) was calculated by dividing change in CBF by change in etCO2. Older adults also underwent neuropsychological assessment of global and domain‐specific cognition. Relationships between dynamic cerebrovascular function, aging, and cognition were analyzed, controlling for hypertension and education. Result: Across age groups, paced breathing decreased etCO2, CBF, and CO2R, while increasing CVR. Breath‐holding increased etCO2, CBF, and CO2R, while decreasing CVR. Older adults demonstrated attenuated cerebrovascular autoregulation (i.e. changes in CBF, CO2R, and CVR) in response to hypo‐ and hypercapnia, despite equivalent changes in etCO2 and blood pressure. Among older adults, weaker cerebrovascular response was associated with worse performance on measures of global cognition, memory, and executive function. Effects were preserved even after controlling for hypertension. Conclusion: Through instigation of mild hypercapnia and hypocapnia during MRI, cerebrovascular reactivity deficits were detected in community‐dwelling older adults. Hemodynamic response was attenuated in older relative to younger individuals, suggesting that acute autoregulatory capacity may diminish with aging, above and beyond changes associated with hypertension. Reduced hemodynamic response was also associated with poorer global cognition and performance on tests of executive function and memory. Results suggest that age‐related vascular changes may hamper the proficiency with which changes in blood pressure and CO2 are met with cerebrovascular responses, potentially compromising CBF and neuronal function. This noninvasive method may therefore enable detection of cerebrovascular changes characterizing the earliest stages of cognitive decline. [ABSTRACT FROM AUTHOR]

Background: Cerebral microvascular pathologies—including white matter lesions, microbleeds and lacunes—are associated with increased risk of vascular dementia and Alzheimer's disease. Despite the role of cerebral microvascular pathological changes in cognitive decline, such changes often remain asymptomatic until pathology progresses to severe stages, and early‐stage markers of cerebrovascular changes are lacking. Elevated levels of circulating endothelial progenitor cells (EPCs) have previously been observed in response to vascular injury and may represent a protective vascular mechanism. However, few previous studies have examined levels of circulating EPCs in older adults with signs of cerebral microvascular pathology. 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. Mononuclear cells were isolated and stained for EPC surface markers CD34, CD133 and CD309. Circulating EPCs were quantified by flow cytometry as the number of cells in the lymphocyte gate positively expressing all three markers (CD34+CD133+CD309+). MRI changes thought to represent microvascular pathologies (white matter hyperintensities, cerebral microbleeds and lacunes) were evaluated and total microvascular disease load was determined using a previously validated score. Result: Fifty‐three older adults (mean age = 69.3 years (SD = 7.5); education = 15.7 years (SD = 2.8); 19 (35.8%) male) were included in this preliminary analysis. Moderate/severe white matter hyperintensity burden was identified by Fazekas scale in 35.8% of participants, small lacunes were identified in 15.1% and microbleeds in 5.7%. Linear regression analyses revealed that older adults with more circulating EPCs exhibited greater total microvascular pathology load (p =.034), after accounting for age, sex and education. Conclusion: Our preliminary findings suggest a role for circulating EPCs as an early‐stage biomarker for cerebral microvascular pathology in older adults free of dementia or stroke symptoms. Novel diagnostic approaches to recognize microvascular changes are needed to identify individuals at risk of dementia before the onset of irreversible cognitive impairment. Longitudinal studies examining the association between EPCs and dementia risk are warranted to further explore the utility of EPCs as a biomarker for cerebral microvascular disease. [ABSTRACT FROM AUTHOR]

Background: Depletion of endothelial progenitor cells (EPCs) has been linked to vascular disease and both mild cognitive impairment (MCI) and Alzheimer's disease (AD) dementia. EPCs have been shown to support oligodendrocyte precursor cell proliferation in the oligovascular niche, suggesting a potential role in protecting white matter (WM) integrity. We studied the relationship between in vitro EPC proliferation and both WM volume and cognitive function. Method: Sixty‐three community dwelling older adults (Mage = 70.94; SDage = 7.39), free of dementia or clinical stroke, underwent venipuncture, neuropsychological testing, and brain MRI. Blood leukocyte fractions were cultured over one week in colony forming unit (CFU)‐Hill media to produce EPCs. On the 5th day, colonies were counted. Cognitive function was measured by a comprehensive neuropsychological battery and the Clinical Dementia Rating (CDR) Scale. WM volumes were measured by Region‐of‐interest (ROI) analysis on T1‐MPRAGE scans using FreeSurfer 5.3. Univariate Analysis of Covariance (ANCOVA) compared CFU‐Hill counts and CDR scores, and multiple linear regression analyses determined the relationship between CFU‐Hill counts, neuropsychological tests and WM ROIs, after controlling for age, sex and education. Result: CFU‐Hill counts were depleted in participants with CDR = 0.5 [F(1, 51) = 5.84, p = 0.02]. Lower CFU‐Hill counts were associated with worse performances on tests of executive functioning [(1) Animals: F(4, 60) = 4.10, p = 0.005; ΔR2 = 0.16; β= 0.41; ΔF = 12.51, p = 0.001; (2) Fruits and Vegetables: F(4, 60) = 4.00, p = 0.006; β=0.36; ΔR2 = 0.12; ΔF = 7.54, p = 0.009; (3) Trails B: F(4, 44)=9.43; p <0.001; β= 0.24; ΔR2 = 0.057; ΔF = 4.69, p = 0.036]. Posterior corpus callosum volume positively predicted CFU‐Hill counts [F(5, 42)=2.62; p =0.038; β= 0.41; ΔR2 = 0.14; ΔF = 7.69, p = 0.008]. Conclusion: Findings suggest EPCs may be linked to impaired cognition and WM volume loss in older adults, potentially implicating EPCs in protecting against vascular‐related WM injury and resulting executive dysfunction. Further studies of EPCs, WM integrity, and executive dysfunction are warranted to evaluate a potential protective role for EPCs in cerebrovascular disease with implications for dementia risk assessment and prevention. [ABSTRACT FROM AUTHOR]

Background: High blood pressure (BP) and low cerebral blood flow (CBF) have been independently related to Alzheimer's disease (AD) pathophysiology. Increased cerebrovascular resistance index (CVRi), the ratio of mean arterial pressure (MAP) to CBF, has also been linked to AD risk in older adults. Autoregulatory mechanisms maintain steady perfusion across a range of MAP values through changes in cerebrovascular resistance in healthy individuals. Age‐dependent cerebrovascular stiffening can disrupt cerebrovascular resistance, leaving the brain vulnerable to hypoperfusion with increased MAP. No studies have evaluated MAP during perfusion MRI to further evaluate whether high BP may be related to lower CBF, and whether this relationship is age‐dependent. We studied MAP during perfusion MRI in a sample of younger and older adults using an MRI‐compatible device to continuously monitor MAP. Method: Community‐dwelling older adults (n=21; age 56‐87) free of dementia or stroke, and healthy younger adults (n=16; age 18‐34) underwent resting pseudo‐continuous arterial spin‐labelling (pCASL)‐MRI to quantify CBF during simultaneous in‐scanner, continuous MAP monitoring. Average MAP and CBF were calculated over the 5 minute scan. Multiple linear regression examined the relationship between MAP and CBF for younger and older adults, controlling for age and sex. Result: Older adults with higher MAP during perfusion MRI exhibited significantly lower CBF levels (R2 =.49, β = ‐.23, p =.02). MAP showed no significant relationship with CBF in younger adults. Conclusion: This is the first study to evaluate MAP during perfusion MRI. Findings indicate that higher MAP is correlated with lower CBF in real time in older adults only. We hypothesize that higher MAP may cause decreased CBF through chronic increases in cerebrovascular resistance. Our approach utilizes pCASL‐MRI, capturing CBF to capillaries and smaller arterioles that are susceptible to age‐related microvascular injury. It remains unclear whether the relationship between MAP and microvascular perfusion plays a role in the increased dementia risk associated with high CVRi, but increased CVRi and decreased CBF are associated with dementia. Future work will explore the role of BP during perfusion MRI and whether it may contribute to diagnosis, prognosis or treatment decision‐making to help prevent dementia. [ABSTRACT FROM AUTHOR]

Introduction: 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: One hundred sixty-one older adults free of dementia or major neurological/psychiatric disorders were recruited. Participants underwent clinical interviews, cognitive testing, venipuncture for Alzheimer's disease (AD) biomarkers, and brain magnetic resonance imaging. Spontaneous CVR was quantified during 5 minutes of rest. Respiratory gases analyzed through nasal cannula to quantify end-tidal carbon dioxide ( ET CO 2 ) levels were used to estimate CVR., 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 AD biomarkers and vascular risk factors., Discussion: Spontaneous CVR deficits in the PHG are observed in older adults with MCI and memory impairment, suggesting medial temporal microvascular dysfunction is observed in cognitive decline., Highlights: Aging is associated with decline in whole brain spontaneous cerebrovascular reactivity (CVR). Older adults with mild cognitive impairment exhibit deficits in spontaneous CVR in the parahippocampal gyrus (PHG). Memory impairment is correlated with reduced spontaneous CVR in the PHG., (© 2024 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

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., Competing Interests: Authors had no conflicts of interest.