Vascular burden and cognition: Mediating roles of neurodegeneration and amyloid-PET

INTRODUCTION: It remains unclear to which extent vascular burden promotes neurodegeneration and cognitive dysfunction in a cohort spanning low-to-severe small vessel disease (SVD) and amyloid-beta pathology. METHODS: In 120 subjects, we investigated 1) whether vascular burden, quantified as total or lobar white matter hyperintensity (WMH) volumes, is associated with different cognitive domains; and 2) whether the total WMH effect on cognition is mediated by amyloid (18F-AV45-PET), glucose metabolism (18F-FDG-PET), and/or cortical atrophy. RESULTS: Increased total WMH volume was associated with poorer performance in all cognitive domains tested, with the strongest effects observed for semantic fluency. These relationships were mediated mainly through cortical atrophy, particularly in the temporal lobe, and to a lesser extent through amyloid and metabolism. WMH volumes differentially impacted cognition depending on lobar location and amyloid status. DISCUSSION: Our study suggests mainly an amyloid-dependent pathway in which vascular burden affects cognitive impairment through temporal lobe atrophy.

Neurodegeneration and Vascular Burden on Cognition After Midlife: A Plasma and Neuroimaging Biomarker Study

Background and Objectives: Neurodegeneration and vascular burden are the two most common causes of post-stroke cognitive impairment. However, the interrelationship between the plasma beta-amyloid (Aβ) and tau protein, cortical atrophy and brain amyloid accumulation on PET imaging in stroke patients is undetermined. We aimed to explore: (1) the relationships of cortical thickness and amyloid burden on PET with plasma Aβ40, Aβ42, tau protein and their composite scores in stroke patients; and (2) the associations of post-stroke cognitive presentations with these plasma and neuroimaging biomarkers.Methods: The prospective project recruited first-ever ischemic stroke patients around 3 months after stroke onset. The plasma Aβ40, Aβ42, and total tau protein were measured with the immunomagnetic reduction method. Cortical thickness was evaluated on MRI, and cortical amyloid plaque deposition was evaluated by 18F-florbetapir PET. Cognition was evaluated with Mini-Mental State Examination (MMSE), Geriatric Depression Scale (GDS), Dementia Rating Scale-2 (DRS-2).Results: The study recruited 24 stroke patients and 13 normal controls. The plasma tau and tau*Aβ42 levels were correlated with mean cortical thickness after age adjustment. The Aβ42/Aβ40 ratio was correlated with global cortical 18F-florbetapir uptake value. The DRS-2 and GDS scores were associated with mean cortical thickness and plasma biomarkers, including Aβ42/Aβ40, tau, tau*Aβ42, tau/Aβ42, and tau/Aβ40 levels, in stroke patients.Conclusion: Plasma Aβ, tau, and their composite scores were associated with cognitive performance 3 months after stroke, and these plasma biomarkers were correlated with corresponding imaging biomarkers of neurodegeneration. Further longitudinal studies with a larger sample size are warranted to replicate the study results.

Cerebrovascular Pathology and Responsiveness to Treatment in Alzheimer’s Disease: A Systematic Review

Introduction: Responsiveness to treatment with cholinesterase inhibitors (ChEIs) is difficult to predict in Alzheimer’s disease (AD). In the current review, vascular burden is considered as a potential moderator of treatment responsiveness. Cerebrovascular burden co-occurs in at least 30% of AD brains, although it is debated if vascular pathology plays a causal or synergistic role in AD pathogenesis. Vascular burden, therefore, could potentially limit response to treatment due to limited brain reserve or augment treatment efficacy as those with vascular pathology may represent a subgroup with comparable clinical expression but less progressed AD neurodegeneration. Methods: A systematic search of Web of Science, Pubmed, Scopus and EthoS identified 32 papers which met the criteria for inclusion. Association of treatment response and vascular burden across five broad markers are discussed: cerebral hypoperfusion, intima-media thickness, white matter changes, cerebral microbleeds and co-existing diagnosis of cerebrovascular disease. Results: Analysis of frontal regional cerebral blood flow and intima-media thickness may have pre- dictive ability to distinguish those with AD who may respond optimally to short-term treatment with ChEIs. The impact of white matter changes is less consistent; the majority of studies demons- trate no association with treatment response and those that do implicate changes in executive func- tioning. There is preliminary evidence that deep cerebral microbleeds limit treatment response in subcortical cognitive domains, but this requires replication. The use of diagnosis of co-occurring cerebrovascular disease yields no robust variability in response to ChEIs in AD. Conclusion: There is limited evidence that markers of cerebral hypoperfusion, intima-media thick- ness and cerebral microbleeds moderate response to ChEIs. Findings for other markers of vascular burden are less consistent and do not support any moderating effect.

Acute Limb Ischemia in Critically ill COVID-19 Patients: a Case Series and Literature Review

Background: The vascular burden increased by COVID-19 infection and including acute limb ischemia (ALI) quickly emerged as a major medical challenge with devastating consequences such as limb loss, multiorgan dysfunction and death. We report a case series of COVID-19 infection associated with ALI to raise awareness and knowledge towards this life-threatening association. Methods: COVIDS-19 patients with acute limb ischemia (ALI) managed in a Moroccan 14 beds COVID-19 ICU between March 2020 and January 2021, were reviewed. Data collected included demographics, clinical presentation, treatments and outcomes. Results: Over the 10-month period, our ICU cared for 407 hospitalized patients with confirmed COVID-19. A total of 6 COVID-19 patients with ALI were identified. The mean age was 61 years (52 - 70) and 5 were men. The most common preexisting condition was diabetes (50%). The mean CRP level was 219 mg/L. Five patients had thrombus in multiple locations. No concomitant deep vein thrombosis was identified. Four patients presented with signs of acute No arterial ischemia with or without respiratory symptoms and were subsequently diagnosed with COVID-19. The remaining two patients developed ischemia during hospitalization. Mean SOFA score was 5 (2 -9). Respiratory support, corticosteroids and heparin therapies were used in all patients. Intubation and vasopressors were required in four patients. Revascularization was performed in five patients and reintervention was necessary in three cases. Four patients died in the ICU while two were successfully discharged. Conclusion: ALI in COVID-19 patients is a challenging life-threatening vascular emergency that requires appropriate multidisciplinary management (intensivists, anesthesiologists, vascular surgeons and interventionists, radiologists, haematologists…) and further studies focused on anticoagulation. Keywords: Acute Limb ischemia, Coagulopathy, COVID-19, SARS-CoV-2, Thrombosis

The Age-Dependent Relationship Between Vascular Risk Factors and Trajectories of Depressed Mood

Cardiovascular risk factors (CVRFs) have been linked to depression, but it is still unclear whether this association becomes stronger or weaker from mid- to later life. Thus, our main aim was to investigate the influence of age on the associations between CRVFs and trajectories of depressed mood. Our sample included 6835 individuals (aged 52–89 years) from the English Longitudinal Study of Ageing (ELSA), who were free of manifest vascular disease at baseline and had bi-yearly measurements of depressed mood over ten years. A composite score incorporated the presence of five CVRFs: hypertension, diabetes, smoking, obesity, and hypercholesterolemia. We used second-order latent growth models to examine the effect of CVRFs, age, and their interaction on levels and changes in depressed mood over time. Our results revealed that baseline CVRFs were associated with higher levels of depressed mood. This association decreased with age and was stronger in midlife compared to later life. CVRFs were not related to changes in depressed mood, indicating that these differences remained stable over time. These findings suggest that CVRFs in midlife, but less so in older age, predict stable differences in depressed mood. They are consistent with reports on the importance of CVRFs in midlife and may support the idea that prevention of vascular burden in this age period may be critical to maintain mental health.

Network Efficiency Mediates the Relationship Between Vascular Burden and Cognitive Impairment

Background and Purpose— Cerebrovascular disease contributes to age-related cognitive decline, but the mechanisms underlying this phenomenon remain incompletely understood. We hypothesized that vascular risk factors would lead to cognitive impairment through the disruption of brain white matter network efficiency. Methods— Participants were 19 346 neurologically healthy individuals from UK Biobank that underwent diffusion MRI and cognitive testing (mean age=62.6). Global efficiency, a measure of network integration, was calculated from white matter networks constructed using deterministic diffusion tractography. First, we determined whether demographics (age, sex, ethnicity, socioeconomic status, and education), vascular risk factors (hypertension, hypercholesterolemia, diabetes mellitus, smoking, body mass index), and white matter hyperintensities were related to global efficiency using multivariate linear regression. Next, we used structural equation modeling to model a multiple regression. The dependent variable was a latent cognition variable using all cognitive data, while independent variables were a latent factor including all vascular risk factors (vascular burden), demographic variables, white matter hyperintensities, and global efficiency. Finally, we used mediation analysis to determine whether global efficiency explained the relationship between vascular burden and cognition. Results— Hypertension and diabetes mellitus were consistently associated with reduced global efficiency even after controlling for white matter hyperintensities. Structural equation models revealed that vascular burden was associated with cognition ( P =0.023), but not after adding global efficiency to the model ( P =0.09), suggesting a mediation effect. Mediation analysis revealed a significant indirect effect of global efficiency on cognition through vascular burden ( P <0.001), suggesting a partial mediation effect. Conclusions— Vascular burden is associated with reduced global efficiency and cognitive impairment in the general population. Network efficiency partially mediates the relationship between vascular burden and cognition. This suggests that treating specific risk factors may prevent reductions in brain network efficiency and preserve cognitive functioning in the aging population.

Vascular burden is associated with a decline in default-mode and global resting-state functional connectivity in individuals at risk for Alzheimer’s disease

IntroductionCross-sectional studies suggest that cardiovascular risk factors and Alzheimer’s disease (AD) biomarkers are associated with abnormal brain resting-state functional connectivity in aging and AD; however, evidence is missing regarding longitudinal changes in functional connectivity. In this study, we investigate whether cholesterol levels and blood pressure are associated with changes in functional connectivity over time in asymptomatic individuals at risk for AD. The analyses were repeated with cerebral β-amyloid (Aβ) and tau deposition in a subset of the participants.MethodsThe study sample included 247 cognitively unimpaired individuals (185 women/ 62 men; mean [SD] age of 63 [5.3] years) of the PREVENT-AD cohort with a parental or multiple-sibling history of sporadic AD. Plasma total-, HDL-, and LDL-cholesterol and systolic and diastolic blood pressure were measured at baseline. Global brain functional connectivity, and connectivity from canonical functional networks, were computed from resting-state functional MRI obtained at baseline and up to four years of annual follow-ups, using a predefined functional parcellation. A subset of participants underwent tau-PET ([18F]Flortaucipir) and Aβ-PET ([18F]NAV4694). Vascular and AD measures were examined as predictors of brain functional connectivity changes in linear mixed-effects models.ResultsHigher total-cholesterol and LDL-cholesterol levels were associated with greater reduction of functional connectivity in the default-mode network over time. In addition, while overall whole-brain functional connectivity showed an increase over time across the entire sample higher diastolic blood pressure was associated with reduction in whole-brain functional connectivity. The associations were similar when the analyses were repeated using two other functional brain parcellations. The findings with total-cholesterol and diastolic blood pressure were also similar but attenuated when performed in a subsample of participants with PET (n=91), whereas AD biomarkers were not associated with changes in functional connectivity over time in this subsample.ConclusionThese findings provide evidence that vascular burden is associated with a decrease in brain functional connectivity over time in older adults with elevated risk for AD. The impact of vascular risk factors on functional brain changes might precede AD pathology-related changes.