Lorenzo Falsetti

The Role of Carotid Atherosclerosis in Alzheimer's Disease Progression

The aim of this 12-month prospective study was to establish whether severe internal carotid artery stenosis is associated with faster progression of the cognitive impairment in patients with Alzheimers disease (AD). Four hundred and eleven patients with AD underwent extracranial carotid Doppler ultrasound evaluation. Cerebrovascular reactivity to hypercapnia was measured by means of the breath-holding index (BHI) in those with severe carotid artery stenosis using transcranial Doppler ultrasonography. Cognitive status was quantified with the Mini Mental State Evaluation (MMSE). Ninety-eight patients had severe carotid artery stenosis, 41 right (group 1), and 57 left (group 2), while 313 had no significant stenosis (group 3). Group 1 and 2 patients showed an increased probability compared with group 3 patients to develop severe dementia (MMSE scores < 21) during the 12-month follow-up period: OR 2.36 (95% CI: 1.14-4.87) and OR 4.90 (95% CI: 2.65-9.04), respectively (p < 0.05, multiple logistic regression analysis). A BHI value ipsilateral to the stenosis < 0.69 predicted a worse MMSE score at 12 months irrespective of the side of the stenosis. These findings suggest that severe internal carotid artery stenosis can be considered as a marker of a faster rate of progression of the cognitive decline in AD. They also indicate that cerebral hemodynamic evaluation could be applied to identify patients at higher risk of rapid cognitive decline, who may benefit from aggressive treatment, and warrant investigation of the advantages of carotid revascularization procedures in these patients.

Vascular predictors of cognitive decline in patients with mild cognitive impairment.

Our aim in this study was to assess the relationship between the state of cerebral vessels and the risk of conversion from mild cognitive impairment (MCI) to Alzheimers disease (AD). We included 117 MCI patients. They underwent an ultrasonographic assessment of common carotid arteries intima-media thickness (IMT) and carotid plaque index. Cerebrovascular reactivity to hypercapnia in the middle cerebral arteries was calculated with the Breath-Holding Index (BHI). After a 12-month follow-up period, neuropsychological examinations demonstrated a progression to dementia in 21 patients. Pathological values of BHI and IMT significantly increased the risk of conversion (BHI: odds ratio, 5.80; 95% confidence interval, 1.83-18.37, p < 0.05; IMT: odds ratio, 3.08; 95% confidence interval, 1.02-9.33; p < 0.05, multinomial logistic regression analysis). Comparison between patients with all normal values and those with the simultaneous alteration of the 2 vascular indexes showed an increase in the risk of conversion from 9% to 33% (ordinal regression analysis). Our findings show that alterations of cerebral vessel functional and anatomic status increase the risk of conversion from MCI to dementia.

Cerebral hemodynamics and cognitive performance in bilateral asymptomatic carotid stenosis

Objectives: To evaluate cognitive performance in subjects with bilateral asymptomatic carotid stenosis (B-ACS) compared to subjects with unilateral ACS and to subjects with no carotid stenosis (CS) and to explore the relationship between cognitive performance and cerebral hemodynamics status in B-ACS. Methods: The neuropsychological investigation included phonemic (ph) and categorical (ca) Verbal Fluency (VF) tests for exploring the left brain functions and Colored Progressive Matrices (CPM) and Complex Figure Copy Test (CFCT) for the right brain. Cerebral hemodynamics status was assessed using the transcranial Doppler–based breath-holding index test. Results: A total of 333 subjects were included: 127 B-ACS, 73/77 left/right unilateral ACS, 56 no CS, mean age 70 ± 3.78 years, 65 male. Subjects with B-ACS and subjects with unilateral ACS showed significantly lower scores in all cognitive tests compared to subjects with no CS (p < 0.05). Subjects with B-ACS with left impaired hemodynamics status showed a significantly reduced ph-VF score, from 13.4 (95% confidence interval [CI] 11.2–15.8) to 7.5 (95% CI 5.4–9.7), and a reduced ca-VF score, from 19.7 (95% CI 18.1–24.1) to 10.8 (95% CI 9.5–15.1), compared to subjects with no CS. Similarly, impaired cerebral hemodynamics in the right side was associated with a significantly reduced CPM score, from an estimated mean of 34.2 (95% CI 29.8–35.4) to 24.6 (95% CI 20.2–25.8), and CFCT score from 37.0 (95% CI 32.0–37.4) to 27.1 (95% CI 23.3–28.7). All comparisons were p < 0.05. Conclusion: Subjects with B-ACS and subjects with unilateral ACS are more likely to have cognitive dysfunction compared to subjects with no CS. There appears to be a link between cognitive dysfunction and hemodynamics impairment due to carotid stenosis.

Blood pressure variability and stroke outcome in patients with internal carotid artery occlusion

PURPOSE The aim of this study was to evaluate the relationship between arterial blood pressure (BP) variability during the acute phase and the 3-month outcome in ischemic stroke patients with internal carotid artery (ICA) occlusion. METHODS At least 10 BP measurements during the first 48 h after stroke onset were obtained in 89 patients with ICA occlusion. BP profile was described using various parameters: average of recordings, maximum (max), minimum (min), difference between max and min (max-min), standard deviation (SD) and coefficient of variation (CV) for both systolic and diastolic BP. Outcome at 3 months was defined using the modified Rankin Scale (mRS) score corrected for baseline stroke severity. RESULTS Fifty-five patients had a good and 34 a poor outcome. Max values, max-min, SD and CV of both systolic and diastolic BP resulted significantly higher in patients with poor outcome compared to those with good outcome (p<0.05, multivariate adjusted model). CONCLUSIONS In a cohort of acute ischemic stroke patients with ipsilateral ICA occlusion BP variability, assessed in the acute phase, was associated with poor clinical outcome. These preliminary exploratory findings are worthy of further study to be conducted to confirm or confute the role of BP variability in predicting stroke outcome. In order to obtain more comprehensive information, it would also be appropriate to consider the possibility of acquiring data related to the pathophysiology of stroke and to cerebral hemodynamic changes.

Vascular Impairment in Alzheimer's Disease: The Role of Obstructive Sleep Apnea

Epidemiological studies have suggested a pathophysiological link between obstructive sleep apnea syndrome (OSAS) and Alzheimers disease (AD). The mechanism by which sleep disturbance can affect cognitive impairment is not clear. The aim of this study was to investigate whether AD patients with OSAS have an impairment in cerebrovascular disease markers. We included 69 patients without OSAS and 93 patients with OSAS. They underwent an ultrasonographic assessment of common carotid arteries intima-media thickness (IMT) and carotid plaque index. Cerebrovascular reactivity to hypercapnia in the middle cerebral arteries was calculated with the Breath-Holding Index (BHI). Pathological values of IMT and BHI were significantly associated with the presence of OSAS (IMT > 1.0 mm: OR 2.98, 95%CI: 1.37-6.46; p < 0.05; BHI < 0.69: OR 5.25, 95%CI: 2.35-11.74; p < 0.05, multivariate adjusted analysis). Furthermore, the extent of cerebrovascular impairment was correlated with the severity of OSAS. The finding of alterations of cerebral vessel functional and anatomic status in AD patients with OSAS suggests the potential for effective treatment for sleep-related disturbances in a subgroup of AD patients.

Cognitive Deterioration in Bilateral Asymptomatic Severe Carotid Stenosis

Background and Purpose— This study aimed to monitor cognitive performance during a 3-year period in subjects with bilateral asymptomatic severe internal carotid artery stenosis and to explore the role of cerebral hemodynamics and atherosclerotic disease in the development of cognitive dysfunction. Methods— One hundred fifty-nine subjects with bilateral asymptomatic severe internal carotid artery stenosis were included and prospectively evaluated for a 3-year period. At entry, demographics, vascular risk profile, and pharmacological treatments were defined. Cognitive status was evaluated using the Mini-Mental State Examination at baseline and at follow-up. Cerebral hemodynamics was assessed by transcranial Doppler–based breath-holding index test. As a measure of the extent of systemic atherosclerotic disease, common carotid artery intima-media thickness was measured. A cutoff for pathological values was set at 0.69 for breath-holding index and 1.0 mm for intima-media thickness. Results— The risk of decreasing in Mini-Mental State Examination score increased progressively from patients with bilaterally normal to those with unilaterally abnormal breath-holding index, reaching the highest probability in patients with bilaterally abnormal breath-holding index (P<0.0001). Pathological values of intima-media thickness did not influence the risk of Mini-Mental State Examination score change. Conclusions— Our findings suggest that patients with asymptomatic bilateral severe internal carotid artery stenosis may be at risk of developing cognitive impairment. The evaluation of the hemodynamic status, besides providing insights about the possible mechanism behind the cognitive dysfunction present in carotid atherosclerotic disease, may be of help for the individuation of subjects deserving earlier and more aggressive treatments.

Markers for the Risk of Progression from Mild Cognitive Impairment to Alzheimer's Disease

BACKGROUND Defining reliable markers of conversion to dementia could be the first step in order to identify appropriate treatment strategies for mild cognitive impairment (MCI) patients. OBJECTIVE To develop a tool able to predict the risk of progression from MCI to Alzheimers disease (AD). METHODS 406 MCI patients were included and followed for a one-year period. Demographic characteristics, vascular risk factors, extent of cerebrovascular lesions, markers of carotid atherosclerosis investigated with an ultrasonographic assessment (plaque index and intima-media thickness) and cerebrovascular reactivity to apnea (breath-holding index) were considered as potential predictors of conversion. RESULTS 106 (26%) MCI patients showed a conversion to AD. Plaque index, intima-media thickness, and breath-holding index were relevant predictors of conversion (p = 0.042; p = 0.003; p < 0.001, multivariate logistic regression analysis). A simplified scoring system was devised based on the magnitude of the estimated multinomial logistic regression β coefficient results. A total score was calculated as the sum of each predictive factor which resulted in a 0-5 range. The optimal cut-off score was ≥3 (sensitivity, 23.6%, 95% CI 15.9%-32.8%; specificity, 97.7%, 95% CI 95.3%-99.1%; positive likelihood ratio, 10.1, 95% CI 4.5%-22.7%; negative likelihood ratio, 0.78, 95% CI 0.70%-0.87%). The AUC was 0.71 (95% CI, 0.65-0.77). CONCLUSIONS Our findings show the possibility to obtain a predictive indicator of the risk of conversion from MCI to dementia by considering the presence of both atherosclerotic changes in the carotid district and impairment of cerebral hemodynamics. Such an approach may allow us to formulate a correct prognosis in more than 70% of patients with amnesic MCI.

Visit-to-visit blood pressure variability in Alzheimer disease.

The aim of this study was to evaluate visit-to-visit blood pressure (BP) variability in a cohort of patients with Alzheimer disease (AD) and healthy controls. Patients with clinically diagnosed mild or moderate AD and cognitively normal controls matched for age and sex were recruited and followed up for 6 months. To characterize the BP status of each individual, mean, maximum and minimum values, SD, and coefficient of variation were obtained for both systolic BP (SBP) and diastolic BP (DBP). Seventy AD patients and 140 controls were enrolled. No meaningful differences were found in prevalence or treatments of various vascular risk factors. AD patients had higher maximum and lower minimum values and greater SD and coefficient of variation of both SBP and DBP. Group differences in mean values were significant only for SBP. In the multiple logistic regression analysis, adjusted for confounding variables, all the indices related to BP variability were significantly associated with AD. Our results show that AD patients have a greater variability of both SBP and DBP in comparison with age-matched cognitive normal controls, suggesting potential implication in the pathogenesis or progression of the disease.

Regional MRI Diffusion, White-Matter Hyperintensities, and Cognitive Function in Alzheimer's Disease and Vascular Dementia

Background and Purpose An increase in brain water diffusivity as measured using magnetic resonance imaging (MRI) has been recently reported in normal-appearing white matter (NAWM) in patients affected by cognitive impairment. However, it remains to be clarified if this reflects an overt neuronal tissue disruption that leads to degenerative or microvascular lesions. This question was addressed by comparing the regional MRI apparent diffusion coefficients (ADCs) of NAWM in patients affected by Alzheimers disease (AD) or vascular dementia (VaD). The relationships of ADCs with the white-matter hyperintensity (WMH) burden, carotid atherosclerosis, and cognitive performance were also investigated. Methods Forty-nine AD and 31 VaD patients underwent brain MRI to assess the WMH volume and regional NAWM ADCs, neuropsychological evaluations, and carotid ultrasound to assess the plaque severity and intima-media thickness (IMT). Results Regional ADCs in NAWM did not differ between VaD and AD patients, while the WMH volume was greater in VaD than in AD patients. The ADC in the anterior corpus callosum was related to the WMH volume, while a greater carotid IMT was positively correlated with the temporal ADC and WMH volume. The memory performance was worse in patients with higher temporal ADCs. Constructional praxis scores were related to ADCs in the frontal, and occipital lobes, in the anterior and posterior corpus callosum as well as to the WMH volume. Abstract reasoning was related to frontal, parietal, and temporal ADCs. Conclusions Our data show that higher regional ADCs in NAWM are associated with microcirculatory impairment, as depicted by the WMH volume. Moreover, regional ADCs in NAWM are differently associated with the neuropsychological performances in memory, constructional praxia, and abstract reasoning domains.

Framingham risk score can predict cognitive decline progression in Alzheimer's disease

The role of vascular factors in influencing cognitive decline has been extensively investigated, and some difficulties in defining their weight in dementia pathogenesis have emerged. The aim of the study was to investigate the relevance of the Framingham cardiovascular risk profile (FCRP) in influencing cognitive deterioration in a population of Alzheimers disease (AD) patients. Two hundred eighty-four consecutive AD patients were enrolled. For each patient, FCRP score was calculated. We did a 1-year follow-up to quantify the cognitive decline by recording changes in the Clinical Dementia Rating score. The FCRP score predicted cognitive deterioration with an area under the curve of 0.63 (95% confidence interval: 0.57-0.69; p < 0.0001). In the subpopulation of patients with a genetic increased predisposition to develop cognitive deterioration and with an advanced vascular impairment, the FCRP predictive value significantly increased with an area under the curve of 0.77 (95% confidence interval: 0.52-0.93; p < 0.05). Our findings show that FCRP can predict the progression of deterioration in AD patients. This was particularly evident in patients with major genetic and atherosclerotic risk factors.