Tomasz Dziedzic

Wallerian degeneration: a major component of early axonal pathology in multiple sclerosis.

Axonal loss is a major component of the pathology of multiple sclerosis (MS) and the morphological basis of permanent clinical disability. It occurs in demyelinating plaques but also in the so‐called normal‐appearing white matter (NAWM). However, the contribution of Wallerian degeneration to axonal pathology is not known. Here, we analyzed the extent of Wallerian degeneration and axonal pathology in periplaque white matter (PPWM) and lesions in early multiple sclerosis biopsy tissue from 63 MS patients. Wallerian degeneration was visualized using an antibody against the neuropeptide Y receptor Y1 (NPY‐Y1R). The number of SMI‐32‐positive axons with non‐phosphorylated neurofilaments was significantly higher in both PPWM and plaques compared to control white matter. APP‐positive, acutely damaged axons were found in significantly higher numbers in plaques compared to PPWM. Strikingly, the number of NPY‐Y1R‐positive axons undergoing Wallerian degeneration was significantly higher in PPWM and plaques than in control WM. NPY‐Y1R‐positive axons in PPWM were strongly correlated to those in the lesions. Our results show that Wallerian degeneration is a major component of axonal pathology in the periplaque white matter in early MS. It may contribute to radiological changes observed in early MS and most likely plays a major role in the development of disability.

Paraoxonase gene polymorphisms and sporadic ALS

Background: The human paraoxonase (PON) gene family consists of three members, PON1, PON2, and PON3, located adjacent to each other on chromosome 7. PON catalytic activity may be influenced by frequent amino acid variants. Chronic exposure to certain chemicals or to environmental factors causing enhanced lipid peroxidation metabolized by paraoxonases may be a risk factor for sporadic ALS (sALS). Objective: The aim of this study was to examine the association between PON1 Q192R, PON1 L55M, and PON2 C311S functional polymorphisms and the risk of sALS in a Polish population. Methods: The authors included 185 patients with a definite or probable diagnosis of sALS (El Escorial Criteria) and 437 healthy controls of similar age and gender. The paraoxonase polymorphisms were studied by PCR and restriction enzyme digestion. Results: Using logistic regression analyses, the C allele of the C311S polymorphism was associated with sALS in dominant and additive models, whereas the R allele of the Q192R polymorphism was associated with sALS in recessive, additive, and dominant models. The authors compared the distribution of haplotypes between cases and controls. The R-C haplotype was overrepresented among cases (odds ratio 3.44, 95% CI: 1.55 to 7.62, p = 0.002). Conclusions: Frequent amino acid variants in the paraoxonase 1 and paraoxonase 2 genes are associated with sporadic ALS in a Polish population.

Intracerebral hemorrhage triggers interleukin-6 and interleukin-10 release in blood.

Background and Purpose— Acute brain insult can cause systemic anti-inflammatory response, including anti-inflammatory cytokine release. The goal of this study was to determine the serum level of interleukin-6, interleukin-10, and interleukin-13 in patients with intracerebral hemorrhage and to correlate cytokine concentrations with stroke severity. Methods— Thirty patients with intraparenchymal hemorrhage and 16 control subjects were included. Serum samples were collected on the second day of hemorrhagic stroke. Cytokine level was measured with the enzyme-linked immunosorbent assay method. Results— Increased serum levels of interleukin-6 and interleukin-10 were detected in stroke patients. Interleukin-6 and interleukin-10 levels were significantly correlated with Glasgow Coma Scale score. In addition, interleukin-6 level correlated with blood volume and mass effect. Conclusions— Intracerebral hemorrhage is associated with systemic release of anti-inflammatory cytokines.

Gene Expression Profiles in Human Ruptured and Unruptured Intracranial Aneurysms: What Is the Role of Inflammation?

Background and Purpose— Mechanisms underlying development and rupture of intracranial aneurysms (IA) are poorly recognized. The majority of studies on human tissue have focused on predefined pathways. We sought to analyze global gene expression patterns of ruptured IA, unruptured IA, and control vessels. Methods— Transcription profiles were studied in human ruptured (n=8) and unruptured (n=6) IA, as well as in control intracranial arteries (n=5), using oligonucleotide microarrays. Real-time reverse-transcription polymerase chain reaction was used for confirmation. Functional analysis for determination of over-represented ontological groups among gene expression profiles was also performed. Results— The expression of 159 genes differed among the studied groups. Compared to the controls, 131 genes showed common directions of change in both IA groups. The most impacted biological processes for IA are: (1) the muscle system; (2) cell adhesion (downregulation); and (3) the immune system and inflammatory response (upregulation). Ruptured and unruptured IA differed in genes involved in immune/inflammatory processes; expression was reduced in ruptured IA. Conclusions— Decreased expression of genes related to muscle system and cell adhesion is important for the development of IA. The role of immune/inflammatory processes is unclear. Inflammation may participate in the healing process within IA while playing a protective role against IA rupture.

Systemic Inflammatory Markers and Risk of Dementia

Inflammation plays an important role in the pathogenesis of Alzheimers disease. This article reviews the results of prospective studies demonstrating that the level of systemic inflammation markers, particularly C-reactive protein and interleukin-6, can predict cognitive decline or dementia. The potential mechanisms linking systemic inflammatory molecules to cognitive decline are also discussed.

Hypercortisolemia in acute stroke is related to the inflammatory response

Hypercortisolemia is thought to be a marker of the stress response following stroke. The aim of this study was to investigate the prevalence and prognostic significance of hypercortisolemia. The circadian variation of cortisol level and the relationship between serum cortisol levels and other stress, inflammatory, and haemostatic markers were also investigated. Seventy consecutive patients with their first ischemic stroke and 24 age- and sex-matched controls were included in the study. Serum cortisol levels (at 6:00 AM, 10:00 AM, 6:00 PM, and 10:00 PM), 24-h urine catecholamine excretion, beta-thromboglobulin levels, and other standard biochemical and haematological parameters were measured on the first day of hospitalisation and in control subjects. Outcome measures used the Barthel Index at Day 30, as well as 30- and 90-day mortality rates. Hypercortisolemia, defined as at least two of the four measurements above the normal range of serum cortisol levels (i.e. >618 nmol/l from the morning samples and >460 nmol/l from the evening samples) was found in 25 (35.7%) of the acute stroke patients and in 3 (12.5%) of the controls (p<0.05). Hypercortisolemia was associated with older age, greater severity of neurological deficit, larger ischemic lesions on CT, and worse prognoses (p<0.05). The study did not find a correlation between serum cortisol levels and other markers of the stress response such as catecholamines excretion and glucose levels. A significant correlation between serum cortisol levels and some markers of the inflammatory response, such as fever, fibrinogen level, white blood cell (WBC) count, and beta-thromboglobulin level, was established in stroke patients. Prognostic significance of hypercortisolemia in acute stroke patients seems to be related to the inflammatory response rather than to the stress response.

Beta-blockers reduce the risk of early death in ischemic stroke

OBJECTIVES Beta-blockers reduce mortality in patients after myocardial infarction. Experimental studies suggest that beta-blockers have also neuroprotective properties. The aim of this study was to assess if use of beta-blockers is associated with reduced risk of early death in ischemic stroke patients. MATERIALS AND METHODS Retrospective data analysis of 841 consecutive patients with acute ischemic stroke admitted to the stroke unit within 24 h after stroke onset. RESULTS 10.6% of patients received beta-blockers during hospitalization. Thirty-day case fatality was significantly lower in patients treated with beta-blockers than in those not treated with beta-blockers (6.8% versus 19.0%, P < 0.01). After adjustment for other prognostic factors, the use of beta-blockers was associated with reduced risk of early death (relative hazard 0.37, 95% confidence interval 0.16-0.84) independently of age, stroke severity, fasting glucose, total cholesterol level and pneumonia. When patients who died of cardiovascular causes were excluded from the analysis, the use of beta-blocker was no longer significantly associated with risk of death (P = 0.12). CONCLUSION In a retrospective series the use of beta-blockers was associated with reduced risk of early death in patients with ischemic stroke.

Transient hyperglycemia in ischemic stroke patients

The aim of the study was to investigate glucose derangement and its short- and long-term prognostic significance in nondiabetic ischemic stroke patients. The study involved 262 consecutive patients, mean age: 70.1+/-12.4 years, with a supratentorial ischemic stroke. The following data were collected: patients characteristics, risk factors, comorbidities, and stroke severity assessed by the Scandinavian Stroke Scale (SSS). Serum glucose levels were measured on admission, on the next, 2nd, 3rd, 5th, 7th and 14th day after stroke onset. The outcome measures on day 30 were mortality and capacity to perform daily activities: the Barthel Index and Rankin Scale. The 1-year survival was estimated by the Kaplan-Meier method. Cox proportional hazards regression was used to assess predictors of 1-year mortality in nondiabetics. Diabetes mellitus was found in 24.8% of patients and transient hyperglycemia in 36.3% of patients. Patients with transient hyperglycemia scored lower on SSS in the subsequent days of assessment than patients with either diabetes mellitus or normoglycemia. They had larger ischemic lesions on computer tomography (CT) than diabetics and had higher 30-day mortality than normoglycemics (p<0.05). One-year mortality was similar in transient hyperglycemics and diabetics, and both were significantly higher than in normoglycemics (p<0.05). A proportional hazards model analysis showed that transient hyperglycemia is not an independent predictor of death within a year after stroke.

Nosocomial infections and immunity: lesson from brain-injured patients.

Of brain-injured patients admitted to intensive care units, a significant number acquires nosocomial infections. Increased susceptibility to infectious agents could, at least partly, be due to transient immunodepression triggered by brain damage. Immune deficiency in patients with severe brain injury primarily involves T cell dysfunction. However, humoral and phagocytic deficiencies are also detectable. Activation of the hypothalamo–pituitary–adrenal axis and the sympathetic nervous system plays a crucial role in brain-mediated immunodepression. In this review we discuss the role of immunodepression in the development of nosocomial infections and clinical trials on immunomodulation in brain-injured patients with hospital-acquired infections.

DD genotype of ACE gene is a risk factor for intracerebral hemorrhage

Genetic factors may play a role in susceptibility to stroke. The angiotensin converting enzyme (ACE) gene is a candidate gene for two phenotypically different types of stroke affecting small perforating arteries: spontaneous intracerebral hemorrhage (SIH) and ischemic stroke due to small vessel disease (SVD). The authors report evidence that ACE gene DD homozygosity of the I/D polymorphism in intron 16 is an independent risk factor for SIH, and not for SVD stroke, in a Polish population.