Shared Molecular Mechanisms among Alzheimer’s Disease, Neurovascular Unit Dysfunction and Vascular Risk Factors: A Narrative Review

Alzheimer’s disease (AD) is the most common type of dementia, affecting 24 million individuals. Clinical and epidemiological studies have found several links between vascular risk factors (VRF), neurovascular unit dysfunction (NVUd), blood-brain barrier breakdown (BBBb) and AD onset and progression in adulthood, suggesting a pathogenetic continuum between AD and vascular dementia. Shared pathways between AD, VRF, and NVUd/BBB have also been found at the molecular level, underlining the strength of this association. The present paper reviewed the literature describing commonly shared molecular pathways between adult-onset AD, VRF, and NVUd/BBBb. Current evidence suggests that VRF and NVUd/BBBb are involved in AD neurovascular and neurodegenerative pathology and share several molecular pathways. This is strongly supportive of the hypothesis that the presence of VRF can at least facilitate AD onset and progression through several mechanisms, including NVUd/BBBb. Moreover, vascular disease and several comorbidities may have a cumulative effect on VRF and worsen the clinical manifestations of AD. Early detection and correction of VRF and vascular disease by improving NVUd/BBBd could be a potential target to reduce the overall incidence and delay cognitive impairment in AD

Impact of atrial fibrillation in critically ill patients admitted to a stepdown unit

Background: Limited data are available on the clinical course of patients with history of atrial fibrillation (AF) when admitted in an intensive care environment. We aimed to describe the occurrence of major adverse events in AF patients admitted to a stepdown care unit (SDU) and to analyse clinical factors associated with outcomes, impact of dicumarolic oral anticoagulant (OAC) therapy impact and performance of clinical risk scores in this setting. Materials and methods: Single-centre, observational retrospective analysis on a population of subjects with AF history admitted to a SDU. Therapeutic failure (composite of transfer to ICU or death) was considered the main study outcome. Occurrence of stroke and major bleeding (MH) was considered as secondary outcomes. The performance of clinical risk scores was evaluated. Results: A total of 1430 consecutive patients were enrolled. 194 (13.6%) reported the main outcome. Using multivariate logistic regression, age (odds ratio [OR]: 1.03, 95% confidence interval [CI]: 1.01-1.05), acute coronary syndrome (OR:3.10, 95% CI: 1.88-5.12), cardiogenic shock (OR:10.06, 95% CI: 5.37-18.84), septic shock (OR:5.19,95%CI:3.29-18.84), acute respiratory failure (OR:2.49, 95% CI: 1.67-3.64) and OAC use (OR: 1.61, 95% CI: 1.02-2.55) were independently associated with main outcome. OAC prescription was associated with stroke risk reduction and to both MH and main outcome risk increase. CHA2 DS2 -VASc (c-index: 0.545, P = .117 for stroke) and HAS-BLED (c-index:0.503, P = .900 for MH) did not significantly predict events occurrence. Conclusions: In critically ill AF patients admitted to a SDU, adverse outcomes are highly prevalent. OAC use is associated to an increased risk of therapeutic failure, clinical scores seem unhelpful in predicting stroke and MH, suggesting a highly individualized approach in AF management in this setting

Validation of a self-reported instrument to assess work-related difficulties in patients with migraine: the HEADWORK questionnaire

Background: The degree to which work-related difficulties are recognized in headache research is poor and often carried out with inadequate information such as "reduced ability to work as usual", which do not capture at all the variety of difficulties and the factors that impact over them. The aim of this paper is to present the validation of the HEADWORK questionnaire, which addresses the amount and severity of difficulties in work-related tasks and the factors that impact over them.Methods: We developed a set of items based on a previous literature review and patients' focus groups and tested it on a wide set of patients with episodic and chronic migraine attending eight different Italian headache centers. HEADWORK factor structure was assessed with exploratory and confirmatory factor analysis; internal consistency and construct validity were addressed as well.Results: The validation sample (N= 373) was mostly composed of patients with episodic migraine without aura (64.3%) and of females (81%). Factor analysis retrieved two different scales: "Work-related difficulties", composed of eleven items which explain 67.1% of the total variance, and "Factors contributing to work difficulties", composed of six items which explain 52.1% of the total variance. Both HEADWORK subscales have good measurement properties, with higher scores being associated to higher disability, lower quality of life, lower productivity, higher headache frequency and pain intensity.Conclusions: HEADWORK is a 17-item, two-scale questionnaire addressing the impact of migraine on work-related difficulties in terms of difficulties in general or specific skills, and the factors contributing to these difficulties, defined as negative impact on work tasks. It can be used to address disability weights for the purpose of calculating the burden of migraine, and to assess the balance between therapeutic and side effects of medication on productivity

Cerebral vascular reactivity and cognitive performance in patients with extracranial asymptomatic carotid stenosis

Background: Preliminary studies have reported cognitive dysfunction in unilateral asymptomatic carotid stenosis (ACS). Impaired cerebral hemodynamic status measured by cerebrovascular reactivity has been associated with cognitive dysfunction in unilateral ACS. Aims: (1) To evaluate cognitive performance in bilateral ACS compared to unilateral ACS and healthy subjects and (2) to explore the relationship between cognitive performance and cerebral hemodynamic status in bilateral ACS. Methods: Asymptomatic patients with ultrasound evidence of bilateral or unilateral ACS (60 %-99 % diameter reduction) were prospectively collected. Healthy subjects (HS) comparable for demographics and vascular risk profile served as controls. A neuropsychological investigation included phonemic and categorical Verbal Fluency (VF) tests to explore the left hemisphere and Colored Progressive Matrices (CPM), and Complex Figure Test Copy (CFTC) tests to explore the right hemisphere. Cerebrovascular reactivity (CVR) to hypercapnia using the transcranial Doppler (TCD) based breath-holding index (BHI) test was performed in each subject. Impaired CVR was defined as a BHI\0.69. Generalized linear multivariate and univariate models were employed to evaluate the mean difference on left and right cognitive test abilities in bilateral ACS patients with left and right preserved or impaired CVR. Vascular risk factors, education years, mini-mental status examination (MMSE), and current medications were included as covariates. Results: 333 consecutive subjects were included: 126 bilateral ACS; 73/75 left/right unilateral ACS; 56 HS; mean age: 70 \ub1 3.78 years; males: 65 %; education years: 10.3 \ub1 3.7; MMSE score: 26.7 \ub1 1.27. Bilateral and unilateral ACS patients showed significantly lower scores in all cognitive tests compared to HS (p\0.05). In the multivariate analysis, among bilateral ACS an impaired CVR in the right side was associated with a significantly reduced CPM score: from an estimated mean of 32.6 [95 % Confidence Interval (CI): 29.8\u201335.4) to 23.0 (95 % CI: 20.2\u201325.8) and the CFTC score from 34.7 (95 % CI: 32.0\u201337.4) to 26.0 (95 % CI: 23.3\u201328.7). Similarly, an impaired CVR on the left side was associated with a reduced phonemic VF score: 13.5 (95 % CI: 11.2\u201315.8) to 7.5 (95 % CI: 5.4\u20139.7) and categorical VF score from 21.1 (95 % CI: 18.1\u201324.1) to 12.3 (95 % CI: 9.5\u201315.1). All comparisons were statistically significant (p\0.05). Conclusions: Patients with unilateral or bilateral ACS are more likely to suffer cognitive dysfunction compared to healthy controls. Impaired CVR predicts the development of cognitive dysfunction in bilateral ACS. A non-invasive assessment of CVR using the TCDbased BHI test may contribute to a more comprehensive risk stratification in these patients