The role of human kallikrein 6, clusterin and adiponectin as potential blood biomarkers of dementia.

OBJECTIVES: Progressive degenerative syndromes which affect brain, altering memory, behavior, cognition and emotion, are commonly defined as dementia. It was suggested that serum human kallikrein 6 (KLK6), clusterin (CLU) and adiponectin (ADPN) in combination with inflammation markers, neuroimaging and neuropsychological testing could assist in discriminating dementia patients from control individuals. Our aim was therefore to compare serum concentrations of KLK6, CLU and ADPN and inflammatory marker, interleukin-6 (IL-6), in patients suffering from Alzheimer's disease (AD), patients with vascular dementia (VAD), cognitively healthy participants (CHP) and those with mild cognitive impairment (MCI). DESIGN AND METHODS: Serum samples were collected from AD, VAD and MCI patients admitted to the University Department of Neurology (Zagreb, Croatia) for regular follow-up. All patients underwent standard neuroimaging procedures including brain CT, neurosonological assessment with intima-media thickness (IMT) and breath holding index (BHI) calculations. Cognitive abilities were tested using standard Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA). Concentrations of KLK6, CLU, ADPN and IL-6 were determined in all serum samples. RESULTS: We have recruited a total of 235 participants, divided in 4 groups: AD (N=70), VAD (N=67), MCI (N=48) and CHP (N=50). Serum concentrations of KLK6 (P=0.137), CLU (P=0.178) and ADPN (P=0.268) did not differ between AD, VAD, MCI and cognitively healthy control group of participants, whereas IL-6 was significantly higher in VAD patients than in AD, MCI and CHP individuals (P=0.014). There was no association between investigated biomarkers and clinical patient parameters. CONCLUSIONS: Serum concentrations of KLK6, CLU and ADPN do not differ between AD, VAD and controls with and without mild cognitive impairment. Higher IL-6 levels in VAD group point to the inflammatory component in the development of vascular dementia. Investigated biomarkers are not associated with neuroimaging findings and neuropsychological patient data.

The association of inflammatory markers with cerebral vasoreactivity and carotid atherosclerosis in transient ischaemic attack.

OBJECTIVES: Inflammatory mediators have an important role in the pathogenesis of stroke. Increased activity of inflammatory mediators initiates the development of atherosclerosis independently of other risk factors, thus compromising brain microcirculation and causing transient ischaemic attack (TIA). The aim of our study was to evaluate the relationship between serum level of cellular adhesion molecules (ICAM-1), interleukin-6 (IL-6) and C-reactive protein (CRP) with carotid intima-media thickness (IMT) and breath-holding index (BHI) in subjects with transient ischaemic attack. We also aimed to assess the difference of those markers between TIA patients and disease-free control individuals. DESIGN AND METHODS: The study included 45 TIA patients and 36 disease-free controls matched for age, gender and vascular risk profile. The degree of carotid atherosclerosis was assessed by colour Doppler with measurements of carotid IMT. Transcranial Doppler (TCD) ultrasound was performed in order to assess BHI. IMT, TCD, BHI and serum concentrations of ICAM-1, IL-6, and CRP were measured for all study subjects. RESULTS: Inflammatory markers IL-6, ICAM-1 and CRP were significantly higher in TIA patients than in disease-free controls (P<0.001, P=0.026, P<0.001, respectively). TIA patients had significantly lower values of BHI and higher IMT relative to disease-free control individuals (P<0.001). CONCLUSIONS: TIA is associated with higher ICAM-1, IL-6 and CRP, pointing to the marked inflammatory response to cerebral ischaemia. Inflammatory markers are associated with higher IMT and lower BHI, indicating the insufficient cerebral perfusion due to the underlying atherosclerotic disease. Our findings highlight the key significance of inflammation in the early response to ischaemia during the transitory ischaemic episode.

Advanced asymptomatic carotid disease and cognitive impairment: an understated link?

Advanced carotid disease is known to be associated with symptomatic cerebrovascular diseases, such as stroke or transient ischemic attack (TIA), as well as with poststroke cognitive impairment. However, cognitive decline often occurs in patients with advanced carotid stenosis without clinically evident stroke or TIA, so it is also suspected to be an independent risk factor for dementia. Neurosonological methods enable simple and noninvasive assessment of carotid stenosis in patients at risk of advanced atherosclerosis. Cognitive status in patients diagnosed with advanced carotid stenosis is routinely not taken into consideration, although if cognitive impairment is present, such patients should probably be called symptomatic. In this paper, we discuss results of some most important studies that investigated cognitive status of patients with asymptomatic advanced carotid disease and possible mechanisms involved in the causal relationship between asymptomatic advanced carotid disease and cognitive decline.

Transcranial Doppler monitoring of middle cerebral artery during verbal stimulation in aphasic patients.

Hemodynamic changes can be noninvasively real-time monitored in stroke patients by means of transcranial Doppler sonography (TCD). The aim of this pilot study was to assess hemodynamic changes in both middle cerebral arteries (MCA) in aphasic stroke patients by means of TCD during verbal stimulation. Eight aphasic patients with stroke in the territory of the left MCA were tested by modified Boston Diagnostic Aphasia Examination (BDAE) within 3 days of stroke onset. Both MCA were monitored simultaneously by means of TCD with 2 MHz probes. Basic MCA mean blood flow velocity (MBFV) values were assessed and monitored during verbal stimulation. Verbal stimulation was performed with 30 photos of objects for daily usage, arranged by function. The same test was performed in 16 right-handed healthy controls. In stroke patients, the mean MBFV were 56 cm/s in the left MCA and 56 cm/s in the right MCA. A mean 30% increase was observed in the left MCA and 22% in the right MCA. In healthy controls, a mean 21.7% increase was observed in the left MCA and 18% in the right MCA. A trend toward higher percentage of MBFV increase was observed in the left MCA during verbal stimulations in aphasic patients as compared to control subjects.

Management of patients with transient ischemic attack (TIA) at Sestre milosrdnice University Hospital Center.

Improved outcomes were observed in transient ischemic attack (TIA) patients after implementation of recommendations for stroke management and after multiple interventions such as public campaigns focused on raising awareness of stroke and reorganization of health services. The aim of this study was to describe reorganization of in-hospital services to improve the management of patients suspected of having TIA or stroke, and to validate these measures with patient outcomes. Data on 5219 patients examined between January 1 and December 31, 2008 at emergency neurology outpatient department were analyzed. Patients were referred by general practitioners, emergency physicians, or were brought by relatives without being previously seen by health services staff. The emergency services department is intended to improve care for TIA patients, providing a short standardized clinical assessment followed by initiation of a comprehensive stroke prevention program. Demographic data, risk factors, stroke type, previous TIA history, ABCD2 scores and admission rates were analyzed. A total of 1057 patients suspected of having stroke or TIA were examined. There were 447 patients with ischemic stroke (mean age 73 +/- 11 years, 196 males) and 99 patients with TIA (mean age 67 +/- 14 years, 55 males). Parenchymal hemorrhage was diagnosed in 56 and subarachnoid hemorrhage in 49 patients, while 406 patients had nonspecific symptoms or other systemic or neurologic diseases. TIA preceded stroke in 29 (6.5%) patients and 197 (44%) patients were examined for worsening of stroke symptoms (133 within 24 hours, 47 within 48 hours, and 17 within 7 days). The mean ABCD2 score was 2.95. In all examined patients, a comprehensive stroke prevention program was started; 427/447 (95%) strokes and 31/99 (31%) TIAs were hospitalized at neurology department. Four (4%) TIA patients developed stroke and were hospitalized, three of them after 2 days (ABCD2 score 3.4 and 5) and one after 7 days (ABCD2 score 5). Preventive measures resulted in a low number of strokes after TIA (< 7%), but a relatively high percentage (44%) of stroke patients ignored initial symptoms and sought medical attention after persistence or worsening of the symptoms.

Vascular characteristics of patients with dementia.

Arterial beta stiffness index is a potential risk factor for increased stroke occurrence. Vascular component appears to be significant in both Alzheimer's disease (AD) and vascular dementia (VAD). We aimed to further explore vascular characteristics of patients with both types of cognitive decline using non-invasive neurosonological methods. There were 38 patients; 16 diagnosed with AD and 22 with VAD. Vascular risk factors were assessed and ultrasound measurements on common carotid artery (CCA) were performed using Aloka ProSound ALPHA 10 with 13 MHz linear probe. Among AD patients there were 5 with arterial hypertension (AH), 3 with atrial fibrillation (AF), 2 with diabetes mellitus (DM), 6 with hyper lipidemia and 1 smoker. Nineteen VAD patients had AH, 6 had AF, 12 had hyper lipidemia and one was diabetic. We found no statistically significant differences between groups regarding average body mass index (BMI), blood pressure, pulse pressure, intima-media thickness (IMT), CCA diameter or arterial beta stiffness indices. However, the trend of BMI increase, slight blood and pulse pressure decrease, CCA diameter increase and beta stiffness index increase was noted in VAD patients. Even though there was no significant difference found among two explored subgroups of patients with dementia, there was a tendency of greater systolic and diastolic diameters noted in VAD as well as greater stiffness, especially when measured in the right CCA. This indicates that VAD patients may have more prominent vascular changes that may help differentiate the type of dementia and further monitor these individuals. Further studies on a larger number of patients are needed support this evidence.

Assessment of subtle cognitive impairment in stroke-free patients with carotid disease.

Carotid disease is a known risk factor for stroke and stroke is a known risk factor for cognitive impairment, but relation between carotid artery stenosis and cognitive function in asymptomatic individuals is less clear. Most patients have only minor complaints of cognitive dysfunction and assessment with usual tests is not sensitive enough. The study included 26 stroke-free patients (15 male and 11 female), mean age 66.3 +/- 8.7 years, with advanced internal carotid artery stenosis or/and occlusion (ICAs/o). Left ICAs/o was present in 11, right ICAs/o in eight, and bilateral ICAs/o in seven patients. History was taken and assessment of risk factors, brain CT scan and neurologic examination were performed. Cognitive functions were tested by use of Mini Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA). All patients were asymptomatic, except for two patients that presented with repeated transient ischemic attack (TIA). In all subjects median MMSE scores were within the normal range (27.5; IQ range 25-29), while mean MoCA scores were abnormal (22.6 +/- 3.4). Patients with left ICAs/o scored slightly better on MoCA (22.9 +/- 3.3) than patients with right ICAs/o (22.4 +/- 4.0). Delayed recall MoCA subtest was impaired in 22/26 patients and visuospatial subtest in 23/26 patients; however, there was no statistically significant difference according to the side of ICAs/o. Patients with the presence of one or two risk factors scored lower on visuospatial/executive MoCA subtests (P = 0.018) as compared with patients with multiple risk factors. MoCA proved to be a sensitive tool for assessment of mild cognitive changes in stroke-free patients with advanced ICAs/o. Decline was most pronounced in visuospatial, executive and short-memory functions.

Serum HDL, LDL and total cholesterol in patients with late-life onset of Alzheimer's disease versus vascular dementia.

Patients with cerebrovascular risk factors are nowadays recognized as being at an increased risk of developing cognitive decline of both types. In this pilot study, we evaluated the levels of cholesterol (total, HDL, LDL) in patients with both vascular dementia (VD) and Alzheimer's type of dementia (AD). Cognitive decline was assessed using Mini Mental State Examination (MMSE) as a standardized method. The study included 66 patients diagnosed with dementia. AD was diagnosed in 43 patients (22 male and 21 female) mean age (+/- SD) 72.79 +/- 8.19 years and VD in 23 patients (mean age +/- SD, 77.43 +/- 7.58 years). In AD group, 18 patients had cholesterol values within the normal range, whereas 25 patients had elevated levels of cholesterol. The mean value of total plasma cholesterol was 5.39 (SD = 1.05), LDL cholesterol 3.33 (SD = 0.95) and HDL cholesterol 1.41 (SD = 0.34). In VD group, 11 patients had cholesterol values within the normal range, whereas 12 patients had elevated levels of cholesterol. In this group, the mean value of total plasma cholesterol was 5.78 (SD = 1.06), HDL cholesterol 1.44 (SD = 0.57) and LDL cholesterol 3.72 (SD = 0.85). Total cholesterol, LDL cholesterol and HDL cholesterol levels were higher in the group of patients with VD, however, the difference was not statistically significant.