Current territorial organization for access to revascularization therapies for acute ischemic stroke in the Veneto region (Italy) from 2017 to 2021.

INTRODUCTION: To evaluate the access to treatments with intravenous thrombolysis (IVT) and/or mechanical thrombectomy (MT) in acute ischemic stroke patients admitted to stroke units (SUs) of Veneto region (Italy) according to current "hub-and-spoke" model from 2017 to 2021. PATIENTS AND METHODS: We retrospectively analyzed data on treatments with IVT and/or MT for stroke patients admitted to the 23 SUs (6 Hubs and 17 Spokes) of the 6 macro-areas including 9 local sanitary units (LSUs) and 2 hospitals. RESULTS: We reported 6093 treatments with IVT alone, 1114 with IVT plus MT, and 921 with MT alone. Number of stroke unit (SU) beds/100,000 inhabitants ranges from 2.3 to 2.8, and no difference was found among different macro-areas. Number of treatments/100,000 inhabitants/year ranges from 19 to 34 for IVT alone, from 2 to 7 for IVT plus MT, and from 2 to 5 for MT alone. Number of IVT alone/SU bed/year ranges from 9 to 21 in the Hub and from 6 to 12 in the Spokes. Rate of IVT plus MT in patients directly arrived in the same LSU's Hub ranges from 50 to 81%, likewise the one of MT alone ranges from 49 to 84%. CONCLUSIONS: Treatment target rates of IVT and MT set by Action Plan for Stroke in Europe 2018-2030 has been globally exceeded in the Veneto region. However, the target rate of MT and access revascularization treatments is heterogeneous among different macro-areas. Further efforts should be made to homogenize the current territorial organization.

Acute revascularization treatments for ischemic stroke in the Stroke Units of Triveneto, northeast Italy: time to treatment and functional outcomes.

It is not known whether the current territorial organization for acute revascularization treatments in ischemic stroke patients guarantees similar time to treatment and functional outcomes among different levels of institutional stroke care. We aimed to assess the impact of time to treatment on functional outcomes in ischemic stroke patients who received intravenous thrombolysis (IVT) alone, bridging (IVT plus thrombectomy), or primary thrombectomy in level 1 and level 2 Stroke Units (SUs) in Triveneto, a geographical macroarea in Northeast of Italy. We conducted an analysis of data prospectively collected from 512 consecutive ischemic stroke patients who received IVT and/or mechanical thrombectomy in 25 SUs from September 17th to December 9th 2018. The favorable outcome measures were mRS score 0-1 and 0-2 at 3 months. The unfavorable outcome measures were mRS score 3-5 and death at 3 months. We estimated separately the possible association of each variable for time to treatment (onset-to-door, door-to-needle, onset-to-needle, door-to-groin puncture, needle-to-groin puncture, and onset-to-groin puncture) with 3-month outcome measures by calculating the odds ratios (ORs) with two-sided 95% confidence intervals (CI) after adjustment for pre-defined variables and variables with a probability value ≤ 0.10 in the univariate analysis for each outcome measure. Distribution of acute revascularization treatments was different between level 1 and level 2 SUs (p < 0.001). Among 182 patients admitted to level 1 SUs (n = 16), treatments were IVT alone in 164 (90.1%), bridging in 12 (6.6%), and primary thrombectomy in 6 (3.3%) patients. Among 330 patients admitted to level 2 SUs (n = 9), treatments were IVT alone in 219 (66.4%), bridging in 74 (22.4%), and primary thrombectomy in 37 (11.2%) patients. Rates of excellent outcome (51.4% vs 45.9%), favorable outcome (60.1% vs 58.7%), unfavorable outcome (33.3% vs 33.8%), and death (9.8% vs 11.3%) at 3 months were similar between level 1 and 2 SUs. No significant association was found between time to IVT alone (onset-to-door, door-to-needle, and onset-to-needle) and functional outcomes. After adjustment, door-to-needle time ≤ 60 min (OR 4.005, 95% CI 1.232-13.016), shorter door-to-groin time (OR 0.991, 95% CI 0.983-0.999), shorter needle-to-groin time (OR 0.986, 95% CI 0.975-0.997), and shorter onset-to-groin time (OR 0.994, 95% CI 0.988-1.000) were associated with mRS 0-1. Shorter door-to-groin time (OR 0.991, 95% CI 0.984-0.998), door-to-groin time ≤ 90 min (OR 12.146, 95% CI 2.193-67.280), shorter needle-to-groin time (OR 0.983, 95% CI 0.972-0.995), and shorter onset-to-groin time (OR 0.993, 95% CI 0.987-0.999) were associated with mRS 0-2. Longer door-to-groin time (OR 1.007, 95% CI 1.001-1.014) and longer needle-to-groin time (OR 1.019, 95% CI 1.005-1.034) were associated with mRS 3-5, while door-to-groin time ≤ 90 min (OR 0.229, 95% CI 0.065-0.808) was inversely associated with mRS 3-5. Longer onset-to-needle time (OR 1.025, 95% CI 1.002-1.048) was associated with death. Times to treatment influenced the 3-month outcomes in patients treated with thrombectomy (bridging or primary). A revision of the current territorial organization for acute stroke treatments in Triveneto is needed to reduce transfer time and to increase the proportion of patients transferred from a level 1 SU to a level 2 SU to perform thrombectomy.

Stroke management during the coronavirus disease 2019 (COVID-19) pandemic: experience from three regions of the north east of Italy (Veneto, Friuli-Venezia-Giulia, Trentino-Alto-Adige).

BACKGROUND: Efficiency of care chain response and hospital reactivity were and are challenged for stroke acute care management during the pandemic period of coronavirus disease 2019 (COVID-19) in North-Eastern Italy (Veneto, Friuli-Venezia-Giulia, Trentino-Alto-Adige), counting 7,193,880 inhabitants (ISTAT), with consequences in acute treatment for patients with ischemic stroke. METHODS: We conducted a retrospective data collection of patients admitted to stroke units eventually treated with thrombolysis and thrombectomy, ranging from January to May 2020 from the beginning to the end of the main first pandemic period of COVID-19 in Italy. The primary endpoint was the number of patients arriving to these stroke units, and secondary endpoints were the number of thrombolysis and/or thrombectomy. Chi-square analysis was used on all patients; furthermore, patients were divided into two cohorts (pre-lockdown and lockdown periods) and the Kruskal-Wallis test was used to test differences on admission and reperfusive therapies. RESULTS: In total, 2536 patients were included in 22 centers. There was a significant decrease of admissions in April compared to January. Furthermore, we observed a significant decrease of thrombectomy during the lockdown period, while thrombolysis rate was unaffected in the same interval across all centers. CONCLUSIONS: Our study confirmed a decrease in admission rate of stroke patients in a large area of northern Italy during the lockdown period, especially during the first dramatic phase. Overall, there was no decrease in thrombolysis rate, confirming an effect of emergency care system for stroke patients. Instead, the significant decrease in thrombectomy rate during lockdown addresses some considerations of local and regional stroke networks during COVID-19 pandemic evolution.

Eslicarbazepine in patients with brain tumor-related epilepsy: a single-center experience.

PURPOSE: Brain tumor-related epilepsy (BTRE) is frequent in patients affected with glioma. Most patients have refractory seizures and require polytherapy. Promising treatment options derive from the development of novel anti-epileptic drugs (AEDs), like Eslicarbazepine (ESL), whose role in BTRE has not yet been explored. Our aim was to report a retrospective cohort of patients affected by BTRE treated with ESL as an adjunctive therapy and to discuss the potential role of this third-generation AED in this clinical context. METHODS: We analyzed a single-center, retrospectively collected cohort of patients affected by glioma and BTRE, treated with ESL as an adjunctive therapy. RESULTS: Analysis included 5 males and 3 females with age ranging from 37 to 75 years (mean = 55.5). Mean baseline Karnofsky performance status was 87.5 (range 70-100). Patients were affected by diffuse astrocytoma (3), low grade oligodendroglioma (2), anaplastic glioma (2) and glioblastoma (1). Mean follow-up was 19 months (range 6-59). Mean dose at the last follow-up was 950 mg daily. Mean weekly seizures in the month before initiation of ESL numbered 17.6 (range 0.25-50). At the last follow-up, mean weekly seizures were 2.2 (range 0-10), i.e. significantly lower than baseline (p = 0.03). The mean reduction of seizures achieved after introduction of ESL was 65%, with 6/8 patients (75%) showing a reduction of more than 50%. Two patients (25%) were seizure free. CONCLUSIONS: This single-center experience suggests that ESL may be a well-tolerated, efficacious option as an add-on drug in the treatment of BTRE.

Intravenous thrombolysis for ischemic stroke in the Veneto region: the gap between eligibility and reality.

Intravenous thrombolysis (IVT) is the treatment of choice for most patients with acute ischemic stroke. According to the recently updated guidelines, IVT should be administered in absence of absolute exclusion criteria. We aimed to assess the proportion of ischemic strokes potentially eligible and actually treated with IVT, and to explore the reasons for not administering IVT. We prospectively collected and analyzed data from 1184 consecutive ischemic stroke patients admitted to the 22 Stroke Units (SUs) of the Veneto region from September 18th to December 10th 2017. Patients were treated with IVT according to the current Italian guidelines. For untreated patients, the reasons for not administering IVT were reported by each center in a predefined model including absolute and/or relative exclusion criteria and other possible reasons. Out of 841 (71%) patients who presented within 4.5 h of stroke onset, 704 (59%) had no other absolute exclusion criteria and were therefore potentially eligible for IVT according to the current guidelines. However, only 323 (27%) patients were eventually treated with IVT. Among 861 (73%) untreated patients, 480 had at least one absolute exclusion criterion, 283 only relative exclusion criteria, 56 only other reasons, and 42 a combination of relative exclusion criteria and other reasons. Our study showed that only 46% (323/704) of the potentially eligible patients were actually treated with IVT in the SUs of the Veneto region. All healthcare professionals involved in the acute stroke pathway should make an effort to bridge this gap between eligibility and reality.

The Oxford cognitive screen (OCS) as an acute predictor of long-term functional outcome in a prospective sample of stroke patients.

The Oxford Cognitive Screen (OCS) was developed to measure cognitive impairment in stroke. Here, we test if the OCS administered acutely in stroke patients provides useful information in predicting long-term functional outcome. A group of first-time stroke patients (n = 74) underwent an acute behavioral assessment comprising the OCS and the NIHSS within one-week post-stroke. Functional outcome was evaluated using the Stroke Impact Scale 3.0 (SIS 3.0) and the Geriatric Depression Scale (GDS) at 6 and 12-months post-stroke. We compared the predictive ability of the OCS and NIHSS, separately or in combination, to predict different domains of behavioral impairment at a chronic evaluation. The OCS accounted for 61% of variance of SIS physical domain, 61% of memory domain, 79% of language domain, 70% of participation domain and 70% of recovery domain. The OCS accounted for a greater percentage of outcome variance than demographics and NIHSS. The most informative predictive model included the combination of demographics, OCS and NIHSS data. The OCS, performed early after stroke, is a strong independent predictor of long-term functional outcome and significantly improves the prediction of outcome when considered alongside the NIHSS and demographics.

Seizures, Edema, Thrombosis, and Hemorrhages: An Update Review on the Medical Management of Gliomas.

Patients affected with gliomas develop a complex set of clinical manifestations that deeply impact on quality of life and overall survival. Brain tumor-related epilepsy is frequently the first manifestation of gliomas or may occur during the course of disease; the underlying mechanisms have not been fully explained and depend on both patient and tumor factors. Novel treatment options derive from the growing use of third-generation antiepileptic drugs. Vasogenic edema and elevated intracranial pressure cause a considerable burden of symptoms, especially in high-grade glioma, requiring an adequate use of corticosteroids. Patients with gliomas present with an elevated risk of tumor-associated venous thromboembolism whose prophylaxis and treatment are challenging, considering also the availability of new oral anticoagulant drugs. Moreover, intracerebral hemorrhages can complicate the course of the illness both due to tumor-specific characteristics, patient comorbidities, and side effects of antithrombotic and antitumoral therapies. This paper aims to review recent advances in these clinical issues, discussing the medical management of gliomas through an updated literature review.

A low-dimensional structure of neurological impairment in stroke.

Neurological deficits following stroke are traditionally described as syndromes related to damage of a specific area or vascular territory. Recent studies indicate that, at the population level, post-stroke neurological impairments cluster in three sets of correlated deficits across different behavioural domains. To examine the reproducibility and specificity of this structure, we prospectively studied first-time stroke patients (n = 237) using a bedside, clinically applicable, neuropsychological assessment and compared the behavioural and anatomical results with those obtained from a different prospective cohort studied with an extensive neuropsychological battery. The behavioural assessment at 1-week post-stroke included the Oxford Cognitive Screen and the National Institutes of Health Stroke Scale. A principal component analysis was used to reduce variables and describe behavioural variance across patients. Lesions were manually segmented on structural scans. The relationship between anatomy and behaviour was analysed using multivariate regression models. Three principal components explained ≈50% of the behavioural variance across subjects. PC1 loaded on language, calculation, praxis, right side neglect and memory deficits; PC2 loaded on left motor, visual and spatial neglect deficits; PC3 loaded on right motor deficits. These components matched those obtained with a more extensive battery. The underlying lesion anatomy was also similar. Neurological deficits following stroke are correlated in a low-dimensional structure of impairment, related neither to the damage of a specific area or vascular territory. Rather they reflect widespread network impairment caused by focal lesions. These factors showed consistency across different populations, neurobehavioural batteries and, most importantly, can be described using a combination of clinically applicable batteries (National Institutes of Health Stroke Scale and Oxford Cognitive Screen). They represent robust behavioural biomarkers for future stroke population studies.

Selective risk factors profiles and outcomes among patients with stroke and history of prior myocardial infarction. The European Community Stroke Project.

BACKGROUND AND OBJECTIVE: Previous myocardial infarction (MI) has been linked with poorer stroke outcome. Whether this depends on a greater stroke severity is still uncertain. The aim of the study was to assess the effect of previous MI on characteristics and outcome of stroke in a large hospital cohort of patients. METHODS: In a European Union Concerted Action, patients hospitalized for first-in-a-lifetime stroke were assessed for demographics, risk factors, clinical presentation, and 3-month survival and handicap. RESULTS: Out of 4190 study patients, 460 (11%) reported a history of MI. Compared with patients without previous MI, those with MI were significantly older, more often males, smokers, alcohol consumers, and with a more severe pre-stroke level of handicap. They had more frequently atrial fibrillation and a history of transient ischemic attack. The acute neurological state and the 28-day mortality did not differ between the two groups. At 3 months, death or severe handicap were more frequent in the MI group (28.3% vs. 21.7%, P=0.001; 74.8% vs. 65.8%, P=0.008). Controlling by logistic regression analysis for age, sex, vascular risk factors, comorbidities, prior to stroke therapy, pre-stroke level of handicap, and clinical acute phase variables, prior MI remained an independent predictor of 3-month death (OR 1.30; 95% CI, 1.02-1.66) and 3-month handicap (OR 1.46; 95% CI, 1.01-2.11). CONCLUSIONS: Previous MI has no impact on clinical severity of acute stroke, but significantly affects 3-month outcome in terms of handicap and mortality.

Risk of rapid global functional decline in elderly patients with severe cerebral age-related white matter changes: the LADIS study.

BACKGROUND: Age-related white matter changes (ARWMCs), frequently detected on neuroimaging, are associated with motor, cognitive, urinary, and mood disorders. The LADIS (LeukoAraiosis and DISability) Study primarily aims to assess ARWMCs as a determinant of global functional decline in the elderly population. METHODS: We enrolled 639 patients (mean age, 74.1 +/- 5.0 years; 45.1% male) referred for nondisabling complaints, who had ARWMCs detected on brain magnetic resonance imaging (MRI) of mild, moderate, or severe grade according to the Fazekas scale. At the 1-year follow-up, 619 were reassessed using the Instrumental Activities of Daily Living (IADL) scale. Of these, 506 were totally independent at baseline, and 113 were impaired in only 1 item of the IADL scale. We studied the 1-year transition to 2 or more activities limited and selective functional impairments as cofactors of functional decline. RESULTS: The rate of transition was 9%, 15%, and 26%, in the mild, moderate, and severe ARWMC group, respectively. Comparing the severe with the mild ARWMC groups and adjusting for age and for other predictors of decline, the risk was more than 2-fold higher (odds ratio; 2.38; 95% confidence interval, 1.29-4.38) in patients with 0 or 1 activity limited, and 3-fold higher (odds ratio, 3.02; 95% confidence interval, 1.34-6.78) among patients fully independent at baseline. Both motor and cognitive deterioration predominantly explained the effect of ARWMCs on global functional decline. CONCLUSION: Elderly patients who are functionally independent and who have severe ARWMCs are at considerable risk of becoming more dependent in a short period, mostly owing to motor and cognitive deterioration.

Differential impact of cerebral white matter changes, diabetes, hypertension and stroke on cognitive performance among non-disabled elderly. The LADIS study.

BACKGROUND AND PURPOSE: Age related white matter changes (ARWMC) are frequent in non-demented old subjects and are associated with impaired cognitive function. Our aim was to study the influence of vascular risk factors and ARWMC on the neuropsychological performance of an independent elderly population, to see if vascular risk factors impair cognition in addition to the effects of ARWMC. METHODS: Independent subjects, aged 65-84 years, with any degree of ARWMC were assessed using a comprehensive neuropsychological battery including the Mini-Mental State Examination (MMSE), VADAS-Cog (Alzheimer's disease assessment scale) and the Stroop and Trail Making test. Vascular risk factors were recorded and ARWMC (measured by MRI) were graded into three classes. The impact of vascular risk factors and ARWMC on neuropsychological performance was assessed by linear regression analyses, with adjustment for age and education. RESULTS: 638 patients (74.1 (5) years old, 55% women) were included. Patients with severe ARWMC performed significantly worse on global tests of cognition, executive functions, speed and motor control, attention, naming and visuoconstructional praxis. Diabetes interfered with tests of executive function, attention, speed and motor control, memory and naming. Arterial hypertension and stroke influenced executive functions and attention. The effect of these vascular risk factors was independent of the severity of ARWMC, age and education. CONCLUSION: ARWMC is related to worse performance in executive function, attention and speed. Diabetes, hypertension and previous stroke influenced neuropsychological performance, independently of the severity of ARWMC, stressing the need to control vascular risk factors in order to prevent cognitive decline in the elderly.

Leukoaraiosis predicts hidden global functioning impairment in nondisabled older people: the LADIS (Leukoaraiosis and Disability in the Elderly) Study.

OBJECTIVES: To determine whether leukoaraiosis severity is independently associated with differences in global functioning in nondisabled elderly patients. DESIGN: Cross-sectional data analysis from an ongoing longitudinal multicenter and multinational study. SETTING: The Leukoaraiosis and Disability Study, a collaboration aimed at assessing leukoaraiosis as an independent predictor of the transition to disability in older people. PARTICIPANTS: Six hundred thirty-nine nondisabled subjects (288 men, 351 women, mean age+/-standard deviation 74.1+/-5.0) with magnetic resonance imaging-detected leukoaraiosis of different severity and presenting with one of the following: mild cognitive or motor disturbances, minor cerebrovascular events, or mood alterations or in whom leukoaraiosis was incidentally identified. MEASUREMENTS: Centralized assessment of leukoaraiosis severity according to the three severity degrees of the Fazekas scale; Disability Assessment for Dementia (DAD) Scale for measurement of global functioning. RESULTS: At baseline, 44% of participants had a mild, 31% a moderate, and 25% a severe degree of leukoaraiosis. A significant trend toward declining performance on the DAD Scale was apparent with increasing leukoaraiosis score severity (total score=98.8, 98.6, 97.5, respectively, in the three leukoaraiosis categories, analysis of variance P=.002). Similar trends were obtained for basic (P=.01) and instrumental (P<.001) function items. The statistical significance of these differences was confirmed in a multiple linear regression analysis correcting for numerous factors known to influence disability in older people. Executive function test performance declined along with increasing leukoaraiosis severity and was significantly related to DAD total score. CONCLUSION: Even in nondisabled elderly patients, levels of functional ability are related to white matter lesion severity. Executive dysfunction may mediate this relationship.

Sex differences in the clinical presentation, resource use, and 3-month outcome of acute stroke in Europe: data from a multicenter multinational hospital-based registry.

BACKGROUND AND PURPOSE: The information on the existence of sex differences in management of stroke patients is scarce. We evaluated whether sex differences may influence clinical presentation, resource use, and outcome of stroke in a European multicenter study. METHODS: In a European Concerted Action involving 7 countries, 4499 patients hospitalized for first-in-a-lifetime stroke were evaluated for demographics, risk factors, clinical presentation, resource use, and 3-month survival, disability (Barthel Index), and handicap (Rankin Scale). RESULTS: Overall, 2239 patients were males and 2260 females. Compared with males, female patients were significantly older (mean age 74.5+/-12.5 versus 69.2+/-12.1 years), more frequently institutionalized before stroke, and with a worse prestroke Rankin score (all values P<0.001). History of hypertension (P=0.007) and atrial fibrillation (P<0.001) were significantly more frequent in female stroke patients, as were coma (P<0.001), paralysis (P<0.001), aphasia (P=0.001), swallowing problems (P=0.005), and urinary incontinence (P<0.001) in the acute phase. Brain imaging, Doppler examination, echocardiogram, and angiography were significantly less frequently performed in female than male patients (all values P<0.001). The frequency of carotid surgery was also significantly lower in female patients (P<0.001). At the 3-month follow-up, after controlling for all baseline and clinical variables, female sex was a significant predictor of disability (odds ratio [OR], 1.41; 95% CI 1.10 to 1.81) and handicap (OR, 1.46; 95% CI 1.14 to 1.86). No significant gender effect was observed on 3-month survival. CONCLUSIONS: Sex-specific differences existed in a large European study of hospital admissions for acute stroke. Both medical and sociodemographic factors may significantly influence stroke outcome. Knowledge of these determinants may positively impact quality of care.

Development of a neuropsychological battery for the Leukoaraiosis and Disability in the Elderly Study (LADIS): experience and baseline data.

The relationship between age-related white matter changes and cognitive performance in independent elderly people is still not clear. The Leukoaraiosis and Disability in the Elderly study (LADIS) involves 11 European centers. It aims to assess the role of the age-related white matter changes as an independent factor in the transition to disability, and in cognitive performance of an independent elderly population. A comprehensive neuropsychological battery was constructed in order to harmonize the cognitive assessment across countries. Patients were evaluated at baseline and during the 3-year follow-up with the Mini-Mental State Examination, a modified version of the VADAS-Cog (Alzheimer's Dementia Assessment Scale plus tests of Delayed recall, Symbol digit, Digit span, Maze, Digit cancellation and Verbal fluency), Trail making and Stroop test. Six hundred thirty-eight patients (mean age 74 +/- 5 years; mean educational level 10 +/- 4, F/M: 351/287) were included in this study. Neuropsychological data were analyzed test by test and also grouped in three compound measures (executive, memory and speed/motor control domains). Older subjects (>74 years) performed significantly worse than younger subjects on the ADAS-Mod and on the tests of memory (t(631) = 3.25; p = 0.001), executive functions (t(581) = 4.68; p = 0.001) and speed/motor control (t(587) = 4.01; p = 0.001). Participants with higher educational level (>8 years of school) showed better performances on the compound measures for memory (t(631) = 3.25; p = 0.001), executive functions (t(581) = 4.68; p = 0.001) and speed/motor control (t(587) = 4.01; p = 0.001). Using multiple regression analysis models to study the influence of demographic variables on cognitive performance, age and education remained important variables influencing test performance. In the LADIS population baseline data, older age and lower educational levels negatively influence neuropsychological performance.

Age, hypertension, and lacunar stroke are the major determinants of the severity of age-related white matter changes. The LADIS (Leukoaraiosis and Disability in the Elderly) Study.

BACKGROUND: Age-related white matter changes (ARWMC), seen on neuroimaging with high frequency in older people, are thought to be consequent to the effect of vascular risk factors and vascular diseases including hypertension and stroke. Among the proofs conventionally required for a factor to be considered a risk factor for a definite pathology, there is the demonstration of a trend in risk exposure related to disease severity. We sought whether such a trend existed in the association of vascular risk factors or comorbidities with the severity of ARWMC aiming particularly at further elucidating the relative roles of hypertension and stroke in this regard. METHODS: The LADIS (Leukoaraiosis and Disability) Study is evaluating the role of ARWMC as an independent determinant of the transition to disability in the elderly. Six hundred and thirty-nine nondisabled subjects (mean age 74.1+/-5.0, M/F: 288/351) with ARWMC of different severity grades on MRI (mild, moderate, or severe according to the Fazekas scale) were assessed at baseline for demographics, vascular risk factors, and comorbidities, and are being followed up for 3 years. RESULTS: Age, frequency of hypertension and history of stroke increased along with increasing ARWMC severity independently of other factors. For hypertension, however, this occurred only in subjects without a stroke history, while for stroke history, it mainly depended on lacunar stroke. The amount of cigarettes smoked and the interaction between hypercholesterolemia and smoking predicted only the most severe ARWMC grade. CONCLUSIONS: The LADIS Study confirms that age, hypertension and lacunar strokes are the major determinants of ARWMC. Smoking and hypercholesterolemia provide additional risk.

Impact of age-related cerebral white matter changes on the transition to disability -- the LADIS study: rationale, design and methodology.

Age-related white matter changes (ARWMC) on brain MRI have been associated with cognitive, motor, mood and urinary disturbances. These factors are known to contribute to disability in elderly people, but the impact of ARWMC and of their progression on the transition to disability is not determined. The LADIS (Leukoaraiosis and Disability in the Elderly) study aims at assessing the role of ARWMC as an independent predictor of the transition to disability in initially nondisabled elderly (65-84 years). Subjects who are not impaired or impaired on only 1 item of the Instrumental Activity of Daily Living (IADL) scale, presenting with different grades of ARWMC severity, were enrolled. Eleven European centers are involved. All the patients were assessed at baseline using an extensive set of clinical and functional tests including global functioning, cognitive, motor, psychiatric and quality of life measures. MRI studies were performed at baseline and will be repeated at the end of the follow-up period to evaluate changes of ARWMC and other lesions. ARWMC were categorized into mild, moderate or severe using the scale of Fazekas et al. For each ARWMC severity class, the primary study outcome is the transition to disability defined as an impairment on 2 or more IADL scale items. Secondary outcomes are the occurrence of dementia, depression, vascular events or death. Six-hundred and thirty-nine subjects (mean age 74.13 +/- 5.0 years, M/F: 288/351) were enrolled in a hospital-based setting and are being followed up for up to 3 years. The large and comprehensive set of measures in LADIS enables a comprehensive description of their functional and clinical features to be examined in relation to different morphological patterns and severity of ARWMC. The longitudinal design will give insight into the possible role of ARWMC and their progression as an independent contributor to disability in the elderly, eventually helping to develop preventive strategies to reduce the burden of disability in late life. The study results may also help to standardize, on an international basis, tools and criteria to identify early stages of disability.

Activities of daily living and global functioning.

Disability is a major negative consequence of aging, with impact on several domains of individual, familial, and social life, and a major source of expenditure for social systems. Preventing or delaying disability in the elderly depends not only on understanding the etiology of pathological processes causing disability, but also on the identification of the early stages of disability (preclinical disability). Vascular dementia may have an impact on disability with variable severity and patterns compared to nonvascular forms of dementia. Vascular cognitive impairment is consistent with a preclinical disability status in which cognitive impairment, already manifested, might not interfere substantially with everyday life activities, but might still cause subtle difficulties in selective performances, like those linked with executive functions. Instruments comprehensive and sensitive enough to describe global function in such a context should be specifically designed and validated.