Cerebrovascular disease (CBVD) is frequently comorbid with autopsy-confirmed Alzheimer disease (AD), but its contribution to the clinical presentation of AD remains unclear. We leveraged the National ...Alzheimer's Coordinating Center (NACC) uniform and neuropathology datasets to compare the cognitive and functional trajectories of AD+/CBVD+ and AD+/CBVD- brain donors.
The sample included NACC brain donors with autopsy-confirmed AD (Braak stage ≥3,
score ≥2) and complete Uniform Data Set (UDS) evaluations between 2005 and 2019, with the most recent UDS evaluation within 2 years of autopsy. CBVD was defined as moderate to severe arteriosclerosis or atherosclerosis. We used propensity score weighting to isolate the effects of comorbid AD and CBVD. This method improved the balance of covariates between the AD+/CBVD+ and AD+/CBVD- groups. Longitudinal mixed-effects models were assessed with robust bayesian estimation. UDS neuropsychological test and the Clinical Dementia Rating Scale Sum of Boxes (CDR-SB) scores were primary outcomes.
Of 2,423 brain donors, 1,476 were classified as AD+/CBVD+. Compared with AD+/CVBD- donors, the AD+/CBVD+ group had accelerated decline (i.e., group × time effects) on measures of processing speed (β = -0.93, 95% CI -1.35, -0.51, Bayes factor BF 130.75), working memory (β = 0.05, 95% CI 0.02, 0.07, BF 3.59), verbal fluency (β = 0.10, 95% CI 0.04, 0.15, BF 1.28), naming (β = 0.09, 95% CI 0.03, 0.16, BF = 0.69), and CDR-SB (β = -0.08, 95% CI -0.12, -0.05, BF 18.11). Effects ranged from weak (BFs <3.0) to strong (BFs <150). We also found worse performance in the AD+/CBVD+ group across time on naming (β = -1.04, 95% CI -1.83, -0.25, BF 2.52) and verbal fluency (β = -0.73, 95% CI -1.30, -0.15, BF 1.34) and more impaired CDR-SB scores (β = 0.45, 95% CI 0.01, 0.89, BF 0.33).
In brain donors with autopsy-confirmed AD, comorbid CBVD was associated with an accelerated functional and cognitive decline, particularly on neuropsychological tests of attention, psychomotor speed, and working memory. CBVD magnified effects of AD neuropathology on semantic-related neuropsychological tasks. Findings support a prominent additive and more subtle synergistic effect for comorbid CBVD neuropathology in AD.
To examine associations of average and change in late-life blood pressure (BP) with cerebrovascular and Alzheimer disease (AD) neuropathology in a large group of decedents followed longitudinally in ...vivo.
This clinical-pathologic study was derived from prospective, community-based cohort studies of aging with similar design and data collection. Measurements of systolic BP (SBP) and diastolic BP (DBP) were obtained annually (mean follow-up 8 years, SD = 4.8). Postmortem neuropathologic evaluations documented diseases of aging. Using regression analyses, we examined associations of average and decline in late-life SBP, and separately in DBP, with neuropathology.
In 1,288 persons (mean age at death = 88.6 years; 65% women), the mean standardized person-specific SBP across the study was 134 (SD = 13) and DBP was 71 (SD = 8) mm Hg. The odds of brain infarcts were increased for participants with a higher mean SBP. Specifically, a person with a 1 SD SBP above the mean (147 vs 134 mm Hg) would have a 46% increased odds of having one or more infarcts, and an increased odds of gross infarct (46%) and microinfarct (36%). Furthermore, a more rapidly declining SBP slope over time increased the odds of one or more infarcts. Mean DBP, not slope, was related to brain infarcts. AD pathology analyses showed an association of a higher mean SBP with higher number of tangles (
= 0.038) but not plaques or other pathology (all
> 0.06). Changes in BP were not significantly related to AD pathology.
Higher average late-life SBP and DBP, and independently a faster decline in SBP, are associated with increasing number of brain infarcts, including gross and microinfarcts. We found some evidence for a relation of SBP with AD, specifically tangles. Both average and decline in BP are related to brain disease.
Blood-brain barrier (BBB) breakdown is observed in older versus younger adults and in late-onset Alzheimer's disease versus age-matched controls, but its causes and consequences in aging are unclear. ...We tested the hypothesis that BBB breakdown is associated with cognitive decline and inflammation in nondemented elders.
Cerebrospinal fluid and serum inflammatory markers were measured using sandwich immunoassays in 120 subjects. Least Absolute Shrinkage and Selection Operator-logistic regression selected cerebrospinal fluid and serum signatures that best classified BBB impairment defined by the cerebrospinal fluid albumin index ≥9. Linear regression examined changes in Clinical Dementia Rating sum of boxes as a function of BBB integrity at baseline.
Mean age was 70 years, mean Mini–Mental State Examination was 27, and BBB impairment was recorded in 13.5%. BBB breakdown was associated with cognitive decline (P = .015). Cerebrospinal fluid intercellular adhesion molecule-1, vascular endothelial growth factor, interleukin-8, serum amyloid A, macrophage derived chemokine, and gender generated an area under the curve of 0.95 for BBB impairment, and serum IL-16, VEGF-D, IL-15, and other variables generated an AUC of 0.92 for BBB impairment.
BBB breakdown is associated with more rapid cognitive decline. Inflammatory mechanisms, including cell adhesion, neutrophil migration, lipid metabolism, and angiogenesis may be implicated.
Varicella zoster virus (VZV) vasculopathy produces stroke secondary to viral infection of cerebral arteries. Not all patients have rash before cerebral ischemia or stroke. Furthermore, other ...vasculitides produce similar clinical features and comparable imaging, angiographic, and CSF abnormalities.
We review our 23 published cases and 7 unpublished cases of VZV vasculopathy. All CSFs were tested for VZV DNA by PCR and anti-VZV IgG antibody and were positive for either or both.
Among 30 patients, rash occurred in 19 (63%), CSF pleocytosis in 20 (67%), and imaging abnormalities in 29 (97%). Angiography in 23 patients revealed abnormalities in 16 (70%). Large and small arteries were involved in 15 (50%), small arteries in 11 (37%), and large arteries in only 4 (13%) of 30 patients. Average time from rash to neurologic symptoms and signs was 4.1 months, and from neurologic symptoms and signs to CSF virologic analysis was 4.2 months. CSF of 9 (30%) patients contained VZV DNA while 28 (93%) had anti-VZV IgG antibody in CSF; in each of these patients, reduced serum/CSF ratio of VZV IgG confirmed intrathecal synthesis.
Rash or CSF pleocytosis is not required to diagnose varicella zoster virus (VZV) vasculopathy, whereas MRI/CT abnormalities are seen in almost all patients. Most patients had mixed large and small artery involvement. Detection of anti-VZV IgG antibody in CSF was a more sensitive indicator of VZV vasculopathy than detection of VZV DNA (p < 0.001). Determination of optimal antiviral treatment and benefit of concurrent steroid therapy awaits studies with larger case numbers.
Abstract Arterial stiffness results from a degenerative process affecting mainly the extracellular matrix of elastic arteries under the effect of aging and risk factors. Changes in extracellular ...matrix proteins and in the mechanical properties of the vessel wall related to arterial stiffening may activate number of mechanisms involved also in the process of atherosclerosis. Several noninvasive methods are now available to estimate large artery stiffness in the clinical setting, including carotid-femoral pulse wave velocity, the reference for aortic stiffness estimate, and local distensibility measures of superficial arteries, namely carotid and femoral. An independent predictive value of arterial stiffness for cardiovascular events has been demonstrated in general as well as in selected populations, and reference values adjusted for age and blood pressure have been established. Thus, arterial stiffness is emerging as an interesting tissue biomarker for cardiovascular risk stratification and estimation of the individual “biological age”. This paper overviews the mechanisms accounting for development and progression of arterial stiffness and for associations between arterial stiffness, atherosclerotic burden and incident cardiovascular events, summarizes the evidence and caveat for clinical use of stiffness as surrogate marker of cardiovascular risk, and briefly outlines some emerging methods for large artery stiffness characterization.
Cerebral blood flow (CBF) regulation is essential for normal brain function. The mammalian brain has evolved a unique mechanism for CBF control known as neurovascular coupling. This mechanism ensures ...a rapid increase in the rate of CBF and oxygen delivery to activated brain structures. The neurovascular unit is composed of astrocytes, mural vascular smooth muscle cells and pericytes, and endothelia, and regulates neurovascular coupling. This Review article examines the cellular and molecular mechanisms within the neurovascular unit that contribute to CBF control, and neurovascular dysfunction in neurodegenerative disorders such as Alzheimer disease.
Transcarotid artery revascularization (TCAR) with the ENROUTE transcarotid neuroprotection and stent system (Silk Road Medical, Inc, Sunnyvale, Calif) combines surgical principles of neuroprotection ...with less invasive endovascular techniques to treat high grade stenosis in the carotid artery. The ENROUTE Neuroprotection System allows the surgeon to directly access the common carotid artery to initiate high rate temporary blood flow reversal to protect the brain while performing carotid angioplasty and stenting. Unprotected catheterization of the arch and lesion is, thus, avoided. Pivotal data from the Safety and Efficacy Study for Reverse Flow Used During Carotid Artery Stenting Procedure (ROADSTER) study of high-risk patients undergoing TCAR have showed a low stroke rate compared with other prospective trials of endovascular carotid intervention. The aim of this article is to provide specific technical details of TCAR.
Low grade inflammation is characterized by raised concentrations of inflammatory markers in the absence of any overt symptoms and is recognized as a risk factor for a number of chronic diseases ...including cancer, cardiovascular, cerebrovascular and neurodegenerative diseases. Many studies suggest that low grade inflammation is mitigated by health promoting behaviours such as healthy eating patterns, physical activity, body weight maintenance and tobacco cessation. To date, large scale studies were mainly focused on circulating markers and little evidence is available on cellular biomarkers. The MOLI‐SANI study is a prospective cohort study that has recruited 24 325 men and women aged ≥35 years from the general population of the Molise Region, a Southern Italian area, with the purpose of investigating genetic and environmental risk/protection factors for cardiovascular and cerebrovascular disease and cancer. Within this cohort, a composite score of low grade inflammation based on the use of plasmatic (C‐reactive protein) and cellular (leukocyte and platelet counts and granulocyte : lymphocyte ratio) biomarkers has been proposed and validated. This score accounts for all possible synergistic effects of such inflammatory markers, thus overcoming any potential bias linked to the multi‐collinearity of these variables. Of notice, the MOLI‐SANI study was the first to address the relationship between the traditional Mediterranean diet and platelet and leucocyte counts as emerging cellular biomarkers of low grade inflammation. The present review paper will discuss the main findings derived from the MOLI‐SANI study on the association of low grade inflammation with a Mediterranean eating pattern, with a particular emphasis on the associated dietary polyphenols.
Atherosclerosis within 2 or more arterial beds has been termed polyvascular disease. Although polyvascular disease has long been associated with heightened cardiovascular risk, much is still unknown ...regarding its pathophysiology and management. In this past decade, the field of cardiovascular disease has experienced exponential growth in terms of antithrombotic and lipid-lowering therapies aimed at mitigating ischemic events. This review describes the inherent risk associated with polyvascular disease in contemporary observational and clinical trial populations and summarizes novel therapies in this high-risk population.
Gut microbiota is emerging as a novel risk factor for atherothrombosis, but the predictive role of gut-derived lipopolysaccharide (LPS) is unknown. We analyzed (1) the association between LPS and ...major adverse cardiovascular events (MACE) in atrial fibrillation (AF) and (2) its relationship with adherence to a Mediterranean diet (Med-diet).
This was a prospective single-center study including 912 AF patients treated with vitamin K antagonists (3716 patient-years). The primary end point was a composite of MACE. Baseline serum LPS, adherence to Med-diet (n=704), and urinary excretion of 11-dehydro-thromboxane B
(TxB
, n=852) were investigated. Mean age was 73.5 years; 42.9% were women. A total of 187 MACE (5.0% per year) occurred: 54, 59, and 74 in the first, second, and third tertile of LPS, respectively (log-rank test
=0.004). Log-LPS (hazard ratio 1.194,
=0.009), age (hazard ratio 1.083,
<0.001), and previous cerebrovascular (hazard ratio 1.634,
=0.004) and cardiac events (hazard ratio 1.822,
<0.001) were predictors of MACE. In the whole cohort, AF (versus sinus rhythm) (β 0.087,
=0.014) and low-density lipoprotein cholesterol (β 0.069,
=0.049) were associated with circulating LPS. Furthermore, Med-diet score (β -0.137,
<0.001) was predictive of log-LPS, with fruits (β -0.083,
=0.030) and legumes (β -0.120,
=0.002) negatively associated with log-LPS levels. Log-LPS and log-TxB
were highly correlated (r=0.598,
<0.001). Log-LPS (β 0.574,
<0.001) and Med-diet score (β -0.218,
<0.001) were significantly associated with baseline urinary excretion of TxB
.
In this cohort of AF patients, LPS levels were predictive of MACE and negatively affected by high adherence to Med-diet. LPS may contribute to MACE incidence in AF by increasing platelet activation.
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