Abstract: BACKGROUND: Hyperglycemia has a detrimental effect in several acute neurological critical illnesses. No consensus exists on the optimal management of hyperglycemia in spontaneous intracerebral hemorrhage (sICH). Our aim was to determine whether blood glucose (BG) would predict 30-day mortality in sICH. METHODS: All patients with a well-defined diagnosis of sICH admitted into 24 h in three primary referred centers were included in this prospective observational follow-up study. Patients had extensive monitoring of BG values and those with BG values >8.29 mmol/l (150 mg/dl) received a variable intravenous insulin dose to maintain BG concentrations during the first 72 h after sICH between 3.32 and 8.29 mmol/l (60-150 mg/dl) using pre-specified insulin dosing schedule protocol. RESULTS: Between January 1, 2002, and December 31, 2003, 295 consecutive patients (mean +/- SD age 66 +/- 12 years) were prospectively included. A 1.0 mmol/l (18 mg/dl) increase in the BG concentration at admission was associated with a 33% mortality increase (OR: 1.33; 95%CI: 1.22-1.46; P < 0.0001). Adjusting for demographics, risk factors, stroke severity, and surgery there was no change in the increased risk. During the first 12 h after sICH, the insulin treatment protocol was enabling to reduce mortality (OR: 1.36, 95%CI: 1.14-1.61; P = 0.0005, per 1 IU increase) while thereafter this association was greatly attenuated and not more significant. CONCLUSIONS: Hyperglycemia is a common condition after sICH and may worsen prognosis. Very early insulin therapy apparently does not improve prognosis. These results raise concern about routine clinical practice implementation of this intervention without any evidence from randomized trials.
Abstract: Idiopathic Parkinson's disease (PD) is a progressive neurodegenerative disease characterized by dopaminergic neuronal loss within the substantia nigra. The incidence and prevalence of PD is rising with an increasing aging population. PD is a slowly progressive condition and patients can develop debilitating motor and functional impairment. Current research has implicated oxidative stress, alpha-synucleinopathy and dysfunction of the ubiquitin-proteasome system in the pathogenesis of PD. A number of gene mutations have also been linked to the development of PD. The elucidation of these new molecular pathways has increased our knowledge of PD pathophysiology. This article reviews important molecular mechanisms and genetic causes implicated in the pathogenesis of PD, which has led to new areas of therapeutic drug research.
Abstract: The ubiquitin-proteasome system (UPS) displays an important cellular quality control function, by removing abnormal proteins from the cytosol, the nucleus and the endoplasmic reticulum. It controls the intracellular levels of short-lived and regulatory proteins, which are important for a variety of basic cellular processes. The pathway involves an enzymatic cascade through which multiple 76-amino acid ubiquitin monomers are covalently attached via a three-step process to the protein substrate, which is then degraded by the 26S proteasome complex. The proteasome is a cylindrical organelle that recognizes ubiquitinated proteins, degrades a large proportion of intracellular proteins, and recycles ubiquitin. Alterations in the proteasome proteolytic pathway have been thought to contribute to protein alterations associated with aging and, in fact, dysregulation of the UPS has been linked to several disease states including neurodegenerative diseases, malignancies, and inflammatory-related disorders. Strong preclinical data now exist supporting the use of reversible proteasome inhibitors to treat a variety of disease states including cancer, autoimmune and inflammatory diseases, myocardial infarction, and ischemic brain injury. Bortezomib (Velcade) has recently been licensed for the treatment of patients with multiple myeloma and is also undergoing further evaluation for the treatment of chronic lymphocytic leukemia (CLL) and a variety of solid tumors. MLN-519 is a small-molecular-weight lactacystin analogue and is being studied for the potential treatment of inflammatory disease and acute stroke. MLN-519 has demonstrated a neuroprotective effect in rat models of middle cerebral artery occlusion by reducing infarct volume, brain oedema and improving neurological outcome with a therapeutic window of up to 6-hrs. This review article focuses on the recent progress in the use of proteasome inhibitors in nervous system diseases with emphasis on the bench-to-bedside research effort which provided the foundation for clinical development of proteasome inhibitors in the treatment of neurological disorders.
Abstract: The mechanisms underlying the pathogenesis of cerebral small vessel disease (SVD) are incompletely understood, although it represents a large burden upon healthcare and social service. New experimental and clinical data suggest that inflammatory reactions may play a crucial role in both the initiation and progression of SVD. Inflammatory processes could be involved in the pathogenesis of SVD, and particularly in the development of white matter lesions and leukoaraiosis. These new data regarding the possible effects of inflammatory reactions in SVD may be of more than just academic interest. It may be that adding evaluation of inflammatory markers, such as C-reactive protein, to conventional risk factors will allow more appropriate preventive and therapeutic interventions.
Abstract: BACKGROUND AND PURPOSE: A clinical grading scale for intracerebral hemorrhage (ICH), formally ICH score, was recently developed showing to predict 30-day mortality in a simple and reliable manner. The aim of the present study was to validate the original ICH (oICH) score in an independent cohort of patients from a developing country assessing 30-day mortality and 6-month functional outcome and whether its modifications can improve prediction. METHODS: Consecutive patients admitted with acute ICH between January 1, 2003, and July 31, 2004, were prospectively included. oICH score was applied and 2 modified ICH (mICH) scores were created with the same variables, except localization, of the oICH score but with different cutoff values. Outcome was assessed as 30-day mortality and 6-month good outcome (Glasgow Outcome Scale [GOS] 4 to 5). RESULTS: A total of 153 patients were included during study period. Thirty-day mortality rate was 34.6% (n=53), and 59 patients (38.6%) had good functional outcome (GOS 4 to 5) at 6 months. The oICH and mICH scores predicted mortality equally well. According to Youden's index (J), the oICH score was a reliable predictor for mortality (J=0.59) but less reliable for predicting good outcome (J=0.54). The mICH scores were equal in predicting mortality but better for predicting good outcome than the oICH score (J=0.60). CONCLUSIONS: oICH score also confirms its validity in a socially and culturally different population. Modifications of oICH do not improve its 30-day mortality prediction but improve its ability to predict good functional outcome at 6 months.
Abstract: Hypertension is the most important modifiable risk factor for ischemic stroke, and antihypertensive treatment is of paramount importance to reduce the incidence of stroke mortality and morbidity. The significance and best management of hypertension during the first hours after stroke onset, however, are still matters of debate. Cerebral ischemia results in a complex inflammatory cascade; inflammatory mechanisms are also important participants in the pathophysiology of hypertension. There has been a convergence of evidence that is important to consider in managing systemic blood pressure after stroke to ensure an optimal outcome. The identification of useful markers will allow progress in our ability to treat blood pressure in the acute phase of a stroke. The determination of levels of C-reactive protein, an acute-phase inflammation marker, may help to guide our approach in the management of blood pressure in acute ischemic stroke. Whether this target will be useful in the development of risk prediction strategies or therapies for the treatment of stroke in humans is far from clear.
Abstract: Proteasomes are large, multi-catalytic protease complexes that are found in the cytosol and in the nucleus of eukaryotic cells with a central role in cellular protein turnover. The ubiquitin-proteasome system (UPS) is the predominant non-lysosomal protein degradation pathway that ensures the viability, proliferation and signaling of eukaryotic organisms. Overwhelming data exist implicating a critical role for the UPS in cerebral ischemic injury. Ischemic and hypoxic trauma, and their associated oxidative, nitrosylative and energetic stress, underlie neurodegeneration following stroke, and evoke a discreet set of transcriptional events which have a complex and interdependent relationship with proteasomal function. Rapid elimination of denatured, misfolded and damaged proteins by the proteasome becomes a critical determinant of cell fate. Proof-of-principle has been obtained from animal models of cerebral ischemia, in which proteasome inhibitors reduce neuronal and astrocytic degeneration, cortical infarct volume, infarct neutrophil infiltration. and nuclear factor kappaB immunoreactivity. This neuroprotective efficacy has also been observed when proteasome inhibitors have been used 6 h after ischemic insult. Strategies aimed at effecting long-lasting changes in proteasomal function are not recommended, given the growing body of evidence implicating long-term proteasomal dysfunction in chronic neurodegenerative disease. These effects are likely due to the fact that the UPS is also essential for cellular growth, metabolism and repair, and untoward effects of proteasomal inhibition indicate that the development of short-lived proteasome inhibitors, or compounds which can spatially and temporally regulate the UPS, is a desirable clinical target. Studies in animal models indicate that the use of specific proteasome inhibitors may be beneficial in treating a host of acute neurological disorders, including ischemic stroke.
Abstract: Metaphore Pharmaceuticals Inc. is developing M-40403, a superoxide dismutase mimetic, for the potential treatment of pain, dermatological disease and inflammation. The company is also investigating the compound for its potential in the treatment for the side effects associated with chemotherapy and radiation therapy.
Abstract: BACKGROUND AND PURPOSE: Several studies have shown, in different populations, that modest elevation of plasma C-reactive protein (CRP) in the range seen in apparently healthy individuals is a strong predictor of future vascular events. Elevated plasma CRP concentrations are also associated with an increased risk of cerebrovascular events and an increased risk of fatal and nonfatal cardiovascular events in ischemic stroke patients. These epidemiological and clinical observations suggest that determination of plasma CRP concentrations could be used as an adjunct for risk assessment in primary and secondary prevention of cerebrovascular disease and be of prognostic value. The aim of this review is to summarize the evidence for CRP as an independent predictor of cerebrovascular events in at-risk individuals and ischemic stroke patients and to consider its usefulness in evaluating prognosis after stroke. SUMMARY OF REVIEW: CRP fulfils most of the requirements of a new risk and prognostic predictor, but several issues await further confirmation and clarification before this marker can be included in the routine evaluation of stroke patients and subjects at risk for cerebrovascular disease. Potentially important associations have been established between elevated plasma CRP concentrations and increased efficacy of established therapies, particularly lipid-lowering therapy with statins. CONCLUSIONS: At present, there is not sufficient evidence to recommend measurement of CRP in the routine evaluation of cerebrovascular disease risk in primary prevention, because there is insufficient evidence as to whether early detection, or intervention based on detection, improves health outcomes, although shared risk of cardiovascular disease indicates this may be of value. In secondary prevention of stroke, elevated CRP adds to existing prognostic markers, but it remains to be established whether specific therapeutic options can be derived from this.
Abstract: Promising findings suggest that systemic inflammation and neuroinflammation are central features in cerebrovascular disease. Inflammatory mechanisms are also important participants in the pathophysiology of hypertension. Markers of inflammation have been shown to be upregulated in different forms of cerebrovascular disease, and to correlate with vascular risk. The inhibitor nuclear factor-kB/nuclear factor-kB system is considered a major intracellular inflammatory pathway, mediating most of the vascular inflammatory responses. Increasing evidence indicates that hypertension, through the vasoactive peptides angiotensin and endothelin-1, promotes and accelerates the atherosclerotic process via inflammatory mechanisms. Proinflammatory properties of angiotensin II have been demonstrated. The identification of useful markers of inflammation, of new therapeutic targets to interfere with these mechanisms, and the evaluation of the efficacy of anti-inflammatory treatments will allow progress in our ability to combat cerebrovascular disease and the complications of hypertension. Whether these targets will be useful in the development of risk prediction strategies or therapies for the treatment of stroke in humans is far from clear.
Abstract: BACKGROUND AND PURPOSE: Proteasomes are large multicatalytic proteinase complexes that are found in the cytosol and in the nucleus of eukaryotic cells with a central role in cellular protein turnover. The ubiquitin-proteasome system (UPS) has a central role in the selective degradation of intracellular proteins. Among the key proteins whose levels are modulated by the proteasome are those involved in the control of inflammatory processes, cell cycle regulation, and gene expression. There are now overwhelming data suggesting that the UPS contributes to cerebral ischemic injury. SUMMARY OF REVIEW: Proteasome inhibition is a potential treatment option for stroke. Thus far, proof of principle has been obtained from studies in several animal models of cerebral ischemia. Treatment with proteasome inhibitors reduces effectively neuronal and astrocytic degeneration, cortical infarct volume, infarct neutrophil infiltration, and NF-kappaB immunoreactivity with an extension of the neuroprotective effect at least 6 hours after ischemic insult. However, it is clear that the UPS represents a central pathway for the processing and metabolism of multiple proteins with critical roles in cellular function. To avoid eliciting significant side effects associated with complete inhibition of the proteasome and the possible immunosuppressive effects from persistent suppression of NF-kappaB activation, it is critical that we understand how to partially and temporally attenuate proteasome function to elicit the desired therapeutic effect before any large-scale use in humans. CONCLUSIONS: This review highlights the most recent advances in our knowledge on UPS, as well as the early experience of using proteasome inhibition strategies to treat acute stroke.
Abstract: In different study populations, several studies have shown that modest C-reactive protein elevation, in the range of apparently healthy individuals, is a strong predictor of future vascular events. Willcox and colleagues summarize the epidemiological and clinical observations that have led to the enthusiastic suggestion that determination of serum C-reactive protein levels could also be used as an adjunct for risk assessment in primary and secondary prevention of cerebrovascular disease. Currently, high-sensitivity C-reactive protein assays as a screening test to ascertain individuals at risk of cerebrovascular disease does not provide an accurate determination of the risk of stroke likelihood, and adequate evidence that early detection improves health outcomes and that an early intervention is likely to have a beneficial impact. High-sensitivity C-reactive protein assays as a screening test, only provide inadequate evidence to be considered as an effective cerebrovascular screening test, especially in the elderly.
Abstract: Although elevated cholesterol levels have been associated with coronary heart disease, the evidence for a role of cholesterol in stroke is less well defined. Epidemiological studies indicate that high lipid levels are linked with an increase in ischemic stroke, while low lipid levels may increase the risk of hemorrhagic stroke. Lipid lowering with statins reduces the incidence of ischemic stroke without increasing the frequency of hemorrhagic stroke. The benefits of statins on stroke may be due to a combination of mechanisms. Statins lower cholesterol levels and reduce the progression of atherosclerotic plaque formation in carotid arteries, and the incidence of emboli from cardiac, aortic and carotid sites. Furthermore, statins may produce cholesterol-independent effects such as improving cerebral blood flow and reducing inflammation and oxidative stress, which could limit the size of an ischemic lesion. Statins offer potential benefits for reducing the incidence and improving the prognosis of stroke.
Abstract: BACKGROUND AND PURPOSE: High levels of C-reactive protein (CRP) are associated with an increased risk of future cardiovascular events in ischemic stroke. It has been hypothesized that the benefit of angiotensin-converting enzyme (ACE) inhibitors in patients at high vascular risk may also result from their anti-inflammatory action. Data evaluating this hypothesis are limited in ischemic stroke. METHODS: We conducted a prospective observational study in 507 patients with first-ever ischemic stroke to analyze the effect of ACE inhibitor treatment at the time of stroke onset on CRP levels within the first 24 hours and the relationship to outcome. Risk estimates were calculated according to Cox regression analysis controlled for blood pressure (BP) levels, clinical and neuroradiological confounding variables, and log-normalized CRP levels at entry. RESULTS: ACE inhibitor treatment was associated with lower (2.6-fold; P<0.0001) median CRP levels and with a reduced 2-year cardiovascular risk (hazard ratio, 0.39; 95% CI, 0.29 to 0.53; P<0.0001) compared with a different BP-lowering regimen. The relationship between ACE inhibitor status and log-normalized CRP levels remained significant (P<0.0001) after we controlled for important confounding variables and concomitant treatments. The reduced risk was also evident in multivariable analysis when ACE inhibitor treatment was controlled for BP, associated risk factors, neuroradiological findings, and concomitant treatments (hazard ratio, 0.43; 95% CI, 0.30 to 0.62; P<0.0001). This risk reduction was greatly attenuated and not more significant when log-normalized CRP levels were included (hazard ratio, 0.67; 95% CI, 0.43 to 1.04; P=0.0721) in the model. CONCLUSIONS: Concomitant treatment with ACE inhibitor at the time of an acute stroke is associated with lower inflammatory response and better long-term outcomes, apparently apart from the effects on BP.
Abstract: Among patients with acute stroke, high blood pressure (BP) and higher levels of circulating C-reactive protein (CRP) at the entry are often associated with poor outcome, although the reason is unclear. If the link between BP and stroke outcome is indeed mediated by inflammatory response, one would expect to see positive associations between BP and CRP. In a prospective observational stroke data bank involving 535 first-ever ischemic stroke patients, we studied the association between BP and baseline concentrations of CRP within 24 hours after stroke onset. The association between BP components and the odds of having an elevated CRP level (> or =1.5 mg/dL) was assessed by logistic regression analysis. An increase in systolic BP (SBP), diastolic BP (DBP), mean arterial pressure (MAP), or pulse pressure (PP) was significantly associated with an increase in the odds of having an elevated CRP level, independent of other associated study factors. For each 10 mm Hg increase in SBP, DBP, MAP, or PP, the odds of having a high CRP level increased by 72% (P<0.0001), 10% (P<0.0001), 21% (P<0.0001), and 10% (P<0.0001), respectively. When the same model was rerun, adjusting for all considered BP components, only SBP significantly increased the odds of an elevated CRP level by 77% (P<0.0001). Increased SBP was significantly associated with elevated levels of circulating CRP in ischemic stroke patients. These findings support a possible role of acute hypertension after stroke as an inflammatory stimulus contributing to ischemic brain inflammation.
Abstract: The ubiquitin-proteasome pathway (UPP) is a predominantly non-lysosomal protein degradation pathway responsible for degrading many critical regulatory proteins (e.g., nuclear factor-kappa B). This pathway is widely known for its ubiquitous role in immune and inflammatory responses, control of cell growth and apoptosis. These roles are apparent in the nervous system, but neurons and their neighboring cells also employ the UPP for distinct functions, ranging from development to the co-ordination of cellular responses, injury of the nervous system and brain-specific processes such as aging and memory. Promising results from preclinical studies in animal models indicate that the use of specific proteasome inhibitors to manipulate UPP may prove valuable in treating such conditions as ischemic stroke.
Abstract: NCX-4016 is a nitric oxide-aspirin conjugate non-steroidal anti-inflammatory drug that is under investigation by NicOx for the potential treatment of cardiovascular disorders and colon cancer. In April 2002, a phase II clinical trial was initiated in symptomatic peripheral arterial disease, and in March 2003, the University of Michigan was awarded a grant by the NIH to conduct a phase II trial in individuals at risk of colon cancer.
Abstract: Millennium Pharmaceuticals Inc (formerly LeukoSite Inc) and PAION GmbH are developing MLN-519, a ubiquitin/proteasome enzyme inhibitor, for the potential treatment of inflammatory diseases and stroke. MLN-519 is currently undergoing phase I clinical trials in acute stroke and myocardial infarction, and is poised to enter phase II trials.
Abstract: BACKGROUND AND PURPOSE: The measurement of markers of inflammation or thrombosis has been proposed as a method to improve the prediction of risk in patients with vascular disease. We evaluated the usefulness of these markers as predictors of cardiovascular events in ischemic stroke patients. METHODS: We analyzed levels of C-reactive protein (CRP), fibrinogen, and D-dimer within the first 24 hours after stroke onset in 473 first-ever ischemic stroke patients and determined the cumulative survival curves free of cardiovascular events in relation to the level of each of these markers according to the Kaplan-Meier method. We adjusted for possible confounding variables using a multivariate Cox proportional-hazards model. RESULTS: Patients in the highest tertiles of D-dimer, fibrinogen, and CRP were associated with an excess risk of new cardiovascular events of 36% (P=0.0134), 63% (P<0.0001), and 72% (P<0.0001), respectively, compared with patients in the lowest tertile. The patients in the highest tertile of CRP had 4 times the risk (hazard ratio, 4.04; P<0.0001) of a new cardiovascular event. Smoking, age, sex, and body mass index did not modify risk, and risk was independent of other confounding variables and of D-dimer and fibrinogen levels. The use of ticlopidine was associated with a significant risk reduction among patients with lower (86%, P=0.0159) and middle (69%, P<0.0001) levels of CRP, whereas a nonsignificant excess risk (27%, P=0.3896) was evident among those with the highest levels. CONCLUSIONS: Elevated levels of CRP, more than of D-dimer and fibrinogen, are related to the risk of new cardiovascular events after ischemic stroke. The efficacy of antiplatelet therapy in secondary prevention appears to be directly related to level of inflammatory and thrombotic markers.
Abstract: BACKGROUND AND PURPOSE: The prognostic influences of fibrinogen and C-reactive protein (CRP) levels and their relations in ischemic stroke have not been well described. The aim of this study was to investigate and compare the 1-year prognostic influences of fibrinogen and CRP levels on outcome in ischemic stroke. METHODS: Fibrinogen and CRP were determined within 24 hours after stroke and related to 1-year outcome in 128 patients with first-ever ischemic stroke. The Kaplan-Meier technique was applied in survival analysis. Multiple logistic regression analysis was used to evaluate the associations between risk factors and outcome. RESULTS: The probabilities of death or new vascular event were 21.1%, 27.9%, and 51.7% (P:=0.0172, chi(2) for trend), respectively, in patients stratified by tertiles of fibrinogen (<3.78, 3.78 to 6.17, and >6.17 g/L). The probabilities of a primary end point were 12.1%, 29.7%, and 54.8% (P:=0.0004), respectively, after stratification of patient data by tertiles of CRP level (<5, 5 to 33, and >33 mg/L). In multiple logistic regression analysis, higher CRP levels (odds ratio, 2.39; 95% CI, 1.28 to 4.49; P:=0.0066) and stroke severity on the Canadian Neurological Stroke Scale (odds ratio, 2.37; 95% CI, 1.01 to 5.58; P:=0.0472) were independently associated with death or new vascular event. CONCLUSIONS: Increased levels of CRP are associated with a worse outcome in patients with ischemic stroke. The increased risk associated with elevated CRP levels is independent of the prognostic influence of fibrinogen.
Abstract: BACKGROUND AND PURPOSE: There is growing evidence of the prognostic importance of C-reactive protein (CRP) in ischemic stroke. However, the independent value of CRP at different stages after stroke has not been established. Therefore, we assessed the prognostic values of CRP in ischemic stroke. We also compared the relation of CRP at admission and discharge with 1-year outcome. METHODS: One hundred ninety-three patients were included in a derivation set (n=128) and a validation set (n=65). Serum CRP was measured, within 24 hours after index ischemic stroke, within 48 to 72 hours, and at hospital discharge. We examined the association between the level of CRP at different stages after stroke and outcome. We adjusted for the possible confounding effect using a multivariate Cox proportional hazard model. RESULTS: A cutoff point of 1.5 mg/dL for CRP at discharge provided optimum sensitivity and specificity for adverse outcome, based on the receiver operator curves. CRP at admission (hazard ratio [HR] 2.78, 95% CI 1.45 to 5.33; P=0.0021) and discharge (HR 9.42, 95% CI 4.27 to 19.05; P<0.0001) were predictors of the combined end point of new vascular events or death at 1 year. CRP at hospital discharge was the strongest independent marker of adverse outcome (HR 7.42, 95% CI 2.75 to 20.03; P=0.0001). These results were confirmed in the validation set (HR 15.66, 95% CI 3.36 to 72.97; P=0.0005). CONCLUSIONS: CRP is a marker of increased 1-year risk in ischemic stroke. CRP at discharge is better related to later outcome and could be of greater utility for risk stratification. These findings are consistent with the hypothesis that elevated CRP may predict future cardiovascular events or death.
Abstract: The type of small-vessel disease in small deep (lacunar) infarcts (SDIs) remains contentious as opposed to that in primary intracerebral haemorrhage (PICH), which is lipohyalinosis in most cases. Therefore, we compared risk factor profiles as indicators of underlying vessel pathology, between patients with SDI and patients with PICH, and those with a non-cardio-embolic infarct involving the cortex (CORTI). Multivariate regression analysis showed the diabetes mellitus [odds ratio (OR) 0.56; 95% confidence interval (CI) 0.34-0.90] and hypercholesterolaemia (OR 0.63; 95% CI 0.40-0.99) were more strongly associated with CORTI than with SDI. Carotid stenosis was associated with SDI in comparison with PICH (OR 7.5; 95% CI 1.02-54.94). Compared with PICH, CORTI was more strongly associated with diabetes mellitus (OR 3.27; 95% CI 1.38-7.76), carotid stenosis (OR 24.42; 95% CI 4.99-119.45), and hypercholesterolaemia (OR 3.12; 95% CI 1.47-6.65), whereas hypertension was associated with PICH (OR 0.37; 95% CI 0.18-0.79). These data support the hypothesis that small-vessel atheromatosis rather than small-vessel lipohyalinosis underlies lacunar infarcts in most cases.
Abstract: BACKGROUND AND PURPOSE: Changes in stroke incidence are likely to occur as a consequence of aging of the population, but evidence for this hypothesis is lacking. METHODS: A prospective community-based registry of first-ever strokes (1994 to 1998) classified according to the International Classification of Diseases, 9th Revision (ICD-9) was established in the L'Aquila district, central Italy, with a total population of 297,838 (1991 census). Patients were identified by active monitoring of multiple sources, including general practitioners. RESULTS: In 1994, 819 patients (398 men and 421 women; mean +/- SD age, 74.8 +/- 11.3 years) suffered from a first-ever stroke. Eighty-nine percent of the patients had neuroimaging studies of the brain and were reclassified with the recent Application of the International Classification of Diseases to Neurology (ICD-10 NA). The occurrence of subarachnoid hemorrhage, intracerebral hemorrhage, cerebral infarction, and ill-defined events was 2.9%, 14.9%, 80.2%, and 2.0%, respectively. Crude annual incidence of first-ever stroke was 2.75/1000 (95% confidence interval [CI], 2.57 to 2.94) and 24.23/1000 (95% CI, 21.65 to 27.10) in patients older than 80 years. Incidence rates were higher in men and steeply increased with age. The standardized rate was 2.37/1000 for the Italian and 2.28/1000 for the European population. The 30-day case-fatality rate was 25.6% (95% CI, 22.8% to 28.7%). The occurrence of death, disability, and full recovery at 1 year was 36.9%, 38.9%, and 24.2%, respectively. No differences were found in stroke incidence and case-fatality according to income and urban or rural residences. CONCLUSIONS: In our population-based study, we found a high stroke incidence notably in the older age subgroups, suggesting that rather than declining, stroke is only being postponed until later in life.
