IL-1α and IL-6 predict vascular events or death in patients with cerebral small vessel disease-Data from the SHEF-CSVD study.

PURPOSE: The natural clinical course of cerebral small vessel disease (CSVD) was not thoroughly described. The aim of this single center cohort study was to establish biochemical predictors of vascular events and death in CSVD patients during a 24-month follow-up. PATIENTS AND METHODS: A total of 130 functionally independent patients with marked MRI features of CSVD and recent lacunar stroke (n = 52,LS), vascular Parkinsonism (n = 28,VaP) or dementia (n = 50,VaD) were prospectively recruited. Serum markers of endothelial dysfunction, inflammation and hemostasis were determined at baseline. The primary outcome was defined as occurrence of death or any vascular events during the observation. RESULTS: The mean age was 72 ± 8.1 years, and 37.6% of the patients were women. The mean follow-up time was 22.3 ± 4.3 months, and 84.6% of patients had extensive white matter lesions on baseline MRI. The overall mortality rate was 6.9%, and vascular events or death occurred in 27% of the patients. Kaplan-Meier survival curves revealed no significant differences between CSVD groups (log rank p = 0.49). Cox regression analysis revealed that IL-1α (HR 1.4; 95%CI 1.09-1.8), IL-6 (1.4;1.1-2.2), hs-CRP (1.1;1.06-1.9), homocysteine (1.4;1.1-1.8), fibrinogen (1.4;1.05-2), and d-dimer (2.7;1.6-4.5) were significantly associated with the primary outcome. IL-1α (1.3;1.07-1.8), IL-6 (1.4;1.02-2.2), d-dimer (2.8;1.6-5) and homocysteine (1.4;1.1-1.8) remained significant after adjusting for age, sex and CSVD radiological markers. CONCLUSIONS: Our study demonstrated the important prognostic role of various circulation markers of inflammation in individuals with different clinical signs and radiological markers of CSVD. The strongest association occurred between IL-1α, IL-6 and recurrent stroke, other vascular events and death.

Cerebral and Extracerebral Vasoreactivity in Patients With Different Clinical Manifestations of Cerebral Small-Vessel Disease: Data From the Significance of Hemodynamic and Hemostatic Factors in the Course of Different Manifestations of Cerebral Small-Vessel Disease Study.

OBJECTIVES: Endothelial dysfunction has been implicated in the pathogenesis of cerebral small-vessel disease (SVD). Little is known about the relationship between SVD and measures of endothelium-dependent vasodilatation and cerebral vasomotor reactivity. The aim of this study was to evaluate cerebral and extracerebral endothelial dysfunction in patients with different manifestations of SVD and to assess the relationship between endothelial dysfunction and radiologic markers of SVD. METHODS: The vasomotor reactivity reserve (VMRr), breath-holding index (BHI) of the middle cerebral arteries, and brachial artery flow-mediated dilatation (FMD) were measured with ultrasound techniques in 90 patients (30 in each group) older than 60 years with extensive white matter lesions (Fazekas grade ≥ 2) with a history of lacunar stroke, vascular dementia, or parkinsonism and 30 individuals with normal magnetic resonance imaging findings (control group). All groups were matched for age, sex, hypertension, and diabetes. RESULTS: The mean age ± SD (71.8 ± 3.4 versus 71.7 ± 3.4 years), sex distribution, and prevalence of the main vascular risk factors were similar in the SVD and control groups. The VMRr (56.6% ± 18.3% versus 77.1% ± 16.9%), BHI (0.8 ± 0.3 versus 1.1 ± 0.4), and FMD (5.8% ± 4 versus 12.1% ± 5.2%) were severely impaired in the SVD groups compared to the control group (P < .01). The vascular responses to all tests was similar in the SVD groups, but they were significantly decreased in patients with severe white matter lesions, marked brain atrophy, and enlarged perivascular spaces. CONCLUSIONS: This study was the first that simultaneously evaluated cerebral and extracerebral vasodilator responses in a well-phenotyped cohort of patients with lacunar stroke, vascular dementia, or parkinsonism. The VMRr, BHI, and FMD were more severely impaired in patients with SVD, regardless of its clinical manifestation, than in control participants. All measures were significantly lower in patients with severe white-matter lesions, brain atrophy, or enlarged perivascular spaces.

The frequency of mitochondrial polymerase gamma related disorders in a large Polish population cohort.

Diseases related to DNA polymerase gamma dysfunction comprise of heterogeneous clinical presentations with variable severity and age of onset. Molecular screening for the common POLG variants: p.Ala467Thr, p.Trp748Ser, p.Gly848Ser, and p.Tre251Ile has been conducted in a large population cohort (n = 3123) and in a clinically heterogeneous group of 1289 patients. Recessive pathogenic variants, including six novel ones were revealed in 22/26 patients. Infantile Alpers-Huttenlocher syndrome and adulthood ataxia spectrum were the most common found in our group. Distinct molecular profile identified in the Polish patients with significant predominance of p.Trp748Ser variant (50% of mutant alleles) reflected strikingly low population frequency of the three remaining variants and slightly higher p.Trp748Ser allele frequency in the general Polish population as compared to the non-Finish European population.

IL-6, PF-4, sCD40 L, and homocysteine are associated with the radiological progression of cerebral small-vessel disease: a 2-year follow-up study.

BACKGROUND: Endothelial dysfunction (ED) is involved in the pathogenesis of cerebral small vessel disease (SVD), however, it is not clear if specific biomarkers related to ED are associated with radiological progression of SVD. METHODS: A single-center, prospective cohort study was conducted among consecutive, adult patients with SVD. Logistic regression was used to analyze the association of each baseline biomarker (highest vs lowest tertile) and the MRI radiological outcome after 2 years. The mean Z-score for vascular inflammation (VI) combined soluble intercellular cell adhesion molecule-1 (sICAM-1), soluble platelet selectin (sP-selectin), CD40 ligand (sCD40 L), platelet factor-4 (PF-4) and homocysteine; Z-score for systemic inflammation (SI) combined high-sensitivity C-reactive protein (hsCRP), interleukin-1α and -6 (IL-1α and IL-6, respectively) and tumor necrosis factor-α (TNF-α). RESULTS: The study group comprised 123 patients (age, mean±SD: 72.2±8 years, 49% females), with lacunar stroke (n=49), vascular dementia (n=48), and vascular parkinsonism (n=26). Moreover, 34.9% patients experienced radiological progression, 43% had progression of isolated white matter lesions (WMLs), 23.2% had new lacunes, and 34.8% had both WMLs progression and new lacunes. After adjustment for confounders (age, sex, blood pressure, MRI lesions load), the PF-4 (OR; 95% CI 5.5; 1.5-21), sCD40L (4.6; 1.1-18.6), IL-6 (7.4; 1.48-37), Z-score for VI (4.5; 1.1-18.6), and, marginally, homocysteine (4.1; 0.99-17) were associated with the risk of any radiological progression; further, homocysteine (2.4; 1.4-14), Z-score for SI (2.1; 1.2-14) and, marginally, IL-6 (6.0; 0.95 -38) were related to the development of new lacunes; PF-4 (7.9; 1.6-38) and, marginally, the Z-score for VI (4.2; 0.9-19.5) were correlated with the risk of WMLs progression. Additional adjustment for clinical SVD manifestations did not significantly alter the results. CONCLUSION: The data supports the concept that ED modulates the radiological progression of SVD and WMLs and lacunes are associated with different inflammatory markers.

Aspirin Resistance: Risk Factors and Prognostic Significance in Patients with Cerebral Small Vessel Disease.

BACKGROUND: The clinical significance of aspirin resistance (AR) in patients with symptomatic cerebrovascular disease is not well known. The aim of this single-center, prospective study was to examine the prevalence, risk factors and prognostic significance of AR in patients with different clinical manifestations of cerebral small vessel disease (CSVD) over 24-month follow-up. METHODS: We studied 104 patients with MRI confirmed CSVD, including those with recent lacunar stroke (LS, n=49), vascular parkinsonism (VaP, n=16) and dementia (VaD, n=39). Platelet aggregation was evaluated with electrode platelet aggregometry (Multiplate analyzer); AR was defined as a value of ≥300 AUC*min. All patients had 24-h ABPM performed at baseline. Radiological progression was recognized based on repeated MRI examinations. RESULTS: The prevalence of AR was 26%, and it did not differ between LS, VaD, and VaP (22.4%, 28.2%, and 31.3%, respectively; p=0.7). The patients with AR had higher triglyceride levels (TG; 144.2±100 vs 109.7±48 mg/dl; p=0.09) and mean arterial blood pressure (MAP; 103.5±15.2 vs 91.7±10.5 mmHg; p<0.01) than did responders to aspirin (RTA). TG (OR 1.02; 95%CI 1-1.11; p=0.04) and MAP (OR 1.03; 95%CI 1.0-1.09; p=0.04) were independent of age, sex, statin and antihypertensive treatment risk factors for AR. The patients with AR more frequently experienced ischemic strokes than did those with RTA (OR 3.1; 98%CI 1.08-9.3; p=0.03) and had more radiological progression (OR 2.2; 95%CI 0.9-5.7; p=0.08). AR was independent of age, sex, baseline Fazekas score predictor of lacunar stroke (OR 3.79; 95%CI 1.19-12; p=0.02) and radiological progression (OR 2.9; 95%CI 1.04-8.3; p=0.04). CONCLUSIONS: The prevalence of AR was high and similar among the patients with LS, VaD, and VaP due to CSVD. Higher 24-h MAP and TG were independently related to the risk of AR. AR was associated with risk of radiological progression and lacunar strokes over 24 months of observation.

Association between hemostatic markers, serum lipid fractions and progression of cerebral small vessel disease: A 2-year follow-up study.

INTRODUCTION: Little is known if hemostatic markers and serum lipid fractions can predict further radiological progression beyond vascular risk factors in cerebral small vessel disease (SVD). We investigated whether they are associated with SVD radiological progression and if they are related to different SVD clinical manifestations. METHODS: A single-center, prospective, cohort study with 2 years of radiological follow-up was performed in consecutive patients with different SVD manifestations. The study group consisted of 123 patients: 49 with lacunar stroke (LS), 48 with vascular dementia (VaD) and 26 with vascular parkinsonism (VaP). We assessed SVD progression by a visual SVD scale. We determined the relationship between serum or plasma concentrations of tissue factor (TF), thrombomodulin, beta-thromboglobulin (BTG), fibrinogen, D-dimer and total cholesterol, HDL-C, LDL-C, triglycerides and SVD progression by logistic regression analysis. RESULTS: 34.9% patients had SVD radiological progression: 43% had isolated WMLs progression, 23.2% had new lacunes, 34.8% had both WMLs progression and new lacunes. Fibrinogen [OR 1.02 (95% CI 1.006-1.011] was significantly associated with risk of new lacunes or WMLs progression regardless of the clinical SVD manifestation. While low HDL [OR 0.96 (0.93-1)] and TF [OR 1.07 (0.99-1.1)] were marginally associated with new lacunes, BTG [OR 1.005 (0.99-1.01)] was associated with WMLs progression. CONCLUSION: We found a relationship between fibrinogen and risk of radiological progression of SVD regardless of the clinical SVD manifestation. In addition, lower HDL and increased TF predicted development of new lacunes, and higher BTG was associated with risk of WMLs progression.

Risk of vascular events in different manifestations of cerebral small vessel disease: A 2-year follow-up study with a control group.

BACKGROUND AND PURPOSE: Natural course of cerebral small vessel disease (CSVD) has not yet been thoroughly studied. The aim of the single center study was to establish risk of vascular events or death in different manifestations of CSVD. METHODS: 150 consecutive, functionally independent patients with marked MRI features of CSVD and with recent lacunar stroke (n = 52, LS), deep hemorrhagic stroke (n = 20, HS), vascular parkinsonism (n = 28, VaP), vascular dementia (n = 50, VaD) and 55 controls (CG) with high atherothrombotic risk free of cerebrovascular events were prospectively recruited and followed for 24 months. RESULTS: Mean age and sex distribution were similar in CSVD and CG but patients with CSVD were less likely to have CAD (19% vs 40%, p = 0.02) and tended to have higher prevalence of diabetes (54% vs 37%, p = 0.11). The risk of vascular events or death was increased in any patients with moderate to severe white matter lesions at baseline MRI (HR 2.0; 95% CI 0.85-7.2), in CSVD (4.56; 95% CI 1.3-14.9) vs CG, regardless of its clinical manifestation: LS or HS (HR 4.70; 95% CI 1.3-16.2) and VaD or VaP (HR 4.59; 95% CI 1.3-15.7). Adjustment for confounders did not change the results substantially. CONCLUSIONS: Patients with symptomatic CSVD regardless of the clinical (acute or chronic) manifestation had more than fourfold the risk of vascular events or death in 24 months of observation compared with controls with high atherothrombotic risk free of cerebrovascular events.

Vascular parkinsonism and vascular dementia are associated with an increased risk of vascular events or death.

INTRODUCTION: The natural course of vascular parkinsonism (VaP) and dementia (VaD) due to cerebral small vessel disease (SVD) is not well known. The aim of this single-center study was to evaluate the long-term risk of vascular events, death and dependency in patients with VaP or VaD and to compare it with patients without cerebrovascular disease but with high atherothrombotic risk. MATERIAL AND METHODS: Seventy-eight consecutive, functionally independent patients with MRI features of SVD and with recently diagnosed VaD (n = 50) and VaP (n = 28) and 55 controls (control group - CG) with high 10-year risk of total cardiovascular disease (SCORE ≥ 5%) were prospectively recruited and followed for 24 months. RESULTS: Patients with SVD had lower prevalence of coronary artery disease compared with the CG (20.5% vs. 40%; p = 0.02) but similar prevalence of other atherothrombotic risk factors including mean age (73.7 ±7.3 vs. 72 ±5.9 years, p = 0.09). All outcomes were worse in SVD patients than controls. Thirty-one percent of SVD patients (34% of VaD vs. 25% of VaP, p = 0.45) experienced vascular events or died compared to 6% of controls (p < 0.01). After adjustments for potential confounders (age, sex, vascular risk factors), patients with VaP (HR = 7.5; 95% CI: 1.6-33; p < 0.01) and VaD (HR = 8.7; 95% CI: 2.1-35; p < 0.01) had higher risk of vascular events or death and death or dependency (respectively; HR = 3.9; 95% CI: 0.83-18.8; p = 0.07 and HR = 4.7, 95% CI: 1.1-19.7; p = 0.03). CONCLUSIONS: Patients with VaP or VaD due to SVD had significantly higher risk of vascular events, death and dependency compared to controls with high cardiovascular risk and without cerebrovascular disease.

[Evaluation of repetitive transcranial magnetic stimulation effectiveness in treatment of psychiatric and neurologic diseases]. / Ocena skutecznosci powtarzalnej przezczaszkowej stymulacji magnetycznej w leczeniu chorób psychiatrycznych i neurologicznych.

Repetitive transcranial magnetic stimulation (rTMS) is a treatment option with proved effectiveness especially in drug resist depression. It is used in functional brain mapping before neurosurgery operations and diagnostic of corticospinal tract transmission. Many studies are performed to evaluate rTMS using in treatment of obsessive - compulsive disorder, schizophrenia, autism, strokes, tinnitus, Alzheimer and Parkinson diseases, cranial traumas. Moreover rTMS was used in treatment of multiple sclerosis, migraine, dystonia. Electromagnetical field generated by rTMS penetrate skin of the scalp and infiltrate brain tissues to a depth of 2 cm, cause neurons depolarization and generating motor, cognitive and affective effects. Depending on the stimulation frequency rTMS can stimuli or inhibit brain cortex. rTMS mechanism of action remains elusive. Probably it is connected with enhancement of neurotransmitters, modulation of signals transductions pathways in Central Nervous System, gene transcription and release of neuroprotective substances. Studies with use of animals revealed that rTMS stimulation can generate brain changes similar to those seen after electric shock therapy without provoking seizures. The aim of presenting study was to analyze actual researches evaluating rTMS use in treatment of psychiatric and neurological diseases.

[Pathogenesis and clinical manifestations of sporadic cerebral small vessel disease]. / Patogeneza i objawy kliniczne sporadycznej choroby malych naczyn mózgowych.

Sporadic small vessel disease (sSVD) is one of the most common vascular disease of the central nervous system (CNS). It is the main cause of lacunar stokes, hemorrhages to deep brain regions and chronic CNS diseases such as vascular parkinsonism and dementia. Beside a high and growing incidence of sSVD especially in the elderly population, the knowledge of ethiopathogenesis and optimal treatment of sSVD have not been established. The article summarizes different clinical manifestations (acute and chronic) as well as heterogenous radiologic changes found in CNS neuroimaging.

Significance of Haemodynamic and Haemostatic Factors in the Course of Different Manifestations of Cerebral Small Vessel Disease: The SHEF-CSVD Study-Study Rationale and Protocol.

Rationale. This paper describes the rationale and design of the SHEF-CSVD Study, which aims to determine the long-term clinical and radiological course of cerebral small vessel disease (CSVD) and to evaluate haemostatic and haemodynamic prognostic factors of the condition. Design. This single-centre, prospective, non-interventional cohort study will follow 150 consecutive patients with different clinical manifestations of CSVD (lacunar ischaemic stroke, vascular dementia, vascular parkinsonism or spontaneous deep, intracerebral haemorrhage) and 50 age- and sex-matched controls over a period of 24 months. The clinical and radiological course will be evaluated basing on a detailed neurological, neuropsychological and MRI examinations. Haemodynamic (cerebral vasoreactivity, 24 h blood pressure control) and haemostatic factors (markers of endothelial and platelet dysfunction, brachial artery flow-mediated dilatation test) will be determined. Discussion. The scheduled study will specifically address the issue of haemodynamic and haemostatic prognostic factors and their course over time in various clinical manifestations of CSVD. The findings may aid the development of prophylactic strategies and individualised treatment plans, which are critical during the early stages of the disease.

cGMP level in idiopathic Parkinson's disease patients with and without cardiovascular disease - A pilot study.

We have previously found that average serum cGMP level in unselected patients with Parkinson's disease (PD), particularly in patients treated with a combination of l-DOPA and the dopamine agonist pergolide mesylate, is markedly higher than that in healthy controls. Here we compared serum cGMP and total testosterone levels between l-DOPA/pergolide mesylate-treated male idiopathic PD patients without and with cardiovascular disease (iPD, n = 10, and iPD-CVD, n = 10, respectively) and age-matched healthy volunteers (n = 10). There was no difference in PD-related disability between the two patient groups as assessed by UPDRS motor score and Hoehn-Yahr staging. Whereas none of the patients showed hypoandrogenemia, PD patients compared to controls revealed significantly lower serum testosterone levels, and iPD-CVD patients showed significantly lower levels than iPD patients. Serum cGMP levels were but moderately while significantly higher in the two groups of PD patients than in the controls, and were the highest in the iPD-CVD group. For all study groups combined, there was a high negative correlation between total testosterone level and cGMP level. Our data indicate that blood total testosterone level is negatively correlated with general health status in PD patients, whereas the reverse is true for blood cGMP level.

Subthalamic deep brain stimulation for the treatment of Parkinson disease.

BACKGROUND AND PURPOSE: The role of subthalamic nucleus deep brain stimulation (STN DBS) in the treatment of Parkinson disease (PD) is well established. The authors present a group of patients diagnosed with PD who were treated with STN DBS. MATERIAL AND METHODS: Between 2008 and 2009, 32 female and 34 male patients with PD were treated with STN DBS. Mean age at implantation was 57 ± 12 years. PD lasted from 6 to 21 years (mean 10 years). Patients were qualified for the surgery according to the CAPSIT-PD criteria. The STN was identified with direct and indirect methods. Macrostimulation and microrecording for STN identification were used in all cases. A unilateral STN DBS system was implanted in two cases and bilateral implantation was performed among rest of the group. Outcome was assessed six months after implantation. Results : The mean reduction of UPDRS III score among 51 patients who underwent follow-up was 45% (5-89%). Reduction of levodopa consumption varied from 15 to 100%. Infection forced the authors to remove the DBS system in one case four months after implantation. Skin erosion above the internal pulse generator was noted in four cases. CONCLUSIONS: Cardinal symptoms of Parkinson's disease can be safely and effectively treated with STN DBS in selected group of patients.

Intravenous insulin therapy in the maintenance of strict glycemic control in nondiabetic acute stroke patients with mild hyperglycemia.

Several reports indicate that mild hyperglycemia (plasma glucose level [PGL] ≥7.0 and ≤10.0 mmol/L [≥126 and ≤180 mg/dL]) is associated with poor prognosis in nondiabetic patients who sustain acute ischemic stroke (AIS). Insulin therapy to maintain PGL <7.0 mmol/L (<126 mg/dL) has been reported to be beneficial in critically ill patients, but the safety and efficacy of this approach in patients with AIS are not well established. In a prospective, open-label study, 50 consecutive nondiabetic patients with AIS admitted within 12 hours of ictus and with a PGL ≥7.0 and ≤10.0 mmol/L (≥126 and ≤180 mg/dL) were randomized to receive either a 24-hour intravenous (IV) insulin infusion (ISI) adjusted to maintain PGL within 4.5-7.0 mmol/L (81-126 mg/dL) (ISI group; n=26) or treatment with subcutaneous insulin if PGL was >10.0 mmol/L (>180 mg/dL) (control group [CG]; n=24). Patients' neurologic status was assessed based on National Institutes of Health Stroke Scale (NIHSS) score at admission, 24 hours and 30 days. The 2 groups did not differ in terms of risk factors for stroke. The mean PGL measured at admission was 8.25±0.9 mmol/L (149±16 mg/dL) in the ISI group and 8.1±0.8 mmol/L (146±14 mg/dL) in the CG (P=.8). After 24 hours, these values dropped to 4.9±0.5 mmol/L (88±9 mg/dL) and 5.5±0.45 mmol/L (99±8 mg/dL), respectively (P < .01). Two patients from the ISI group (8%) required IV glucose infusion for symptomatic hypoglycemia. There was no significant between-group difference in neurologic status at admission (median NIHSS score, 10±3 vs 10±2) and 24 hours later (8±2 vs 9±3). At 30 days, the median NIHSS score was 4±3 in the ISI group and 7±4 in the CG (P=.04). Our findings indicate that in nondiabetic AIS patients with mild hyperglycemia, IV insulin therapy aimed at maintaining strict glycemic control (PGL 4.5-7.0 mmol/L [81-126 mg/dL]) is relatively safe and may improve stroke outcome.

[Red ear syndrome - a case report]. / Zespól czerwonego ucha - opis przypadku.

The red ear syndrome was first described by Lance in 1994. Since the initial description, approximately 60 cases have been presented in the literature. The syndrome is characterized by attacks of unilateral ear discomfort or burning during which the ear becomes red. An association with upper cervical spine disorders, primary headaches and trigeminal and glossopharyngeal neuralgia was reported. Some cases were idiopathic. We report a new case of red ear syndrome that responded to greater auricular nerve blockade. The literature on the entity is reviewed and a unifying pathophysiological hypothesis of this syndrome is suggested.

Serum interleukin (IL-2, IL-10, IL-6, IL-4), TNFalpha, and INFgamma concentrations are elevated in patients with atypical and idiopathic parkinsonism.

We investigated serum levels of interleukin (IL)-2, IL-10, IL-6, IL-4, TNFalpha, INFgamma in 7 patients with atypical parkinsonism (AP), 31 idiopathic PD (iPD) patients, 17 idiopathic PD with cardiovascular risk factor (iPD-CVRF) patients, and 20 age-matched controls (healthy, non-parkinsonian patients). Cytokine concentrations were measured using the Becton Dickinson (BD) human Th1/Th2 Cytokine kit II with a flow cytometry system. The concentrations of IL-2, IL-10, IL-4, IL-6, TNFalpha, and INFgamma were detectable in the serum from all groups, including the control. Increased serum IL-2, IL-10, IL-4, IL-6, TNFalpha, and INFgamma concentrations were found in all groups of parkinsonian patients, as compared to the control group. The highest elevations of serum IL-2, IL-4, IL-6, TNFalpha, and INFgamma concentrations were observed in AP patients, as compared to the iPD and iPD-CVRF groups. However, the serum IL-6 concentration was higher in the iPD-CVRF group than in the iPD group. The IL-10 level was significantly higher in all groups of PD patients relative to the control group, but was the lowest in the serum from the AP patients. Moreover, the serum levels of lipid peroxidation products were enhanced 2.1- and 1.5-fold in AP and both iPD groups, respectively. These results argue in favor of the involvement of immunological events in the process of neurodegeneration in AP and PD.