Alessia Lanari

Early Hemorrhagic Transformation of Brain Infarction: Rate, Predictive Factors, and Influence on Clinical Outcome Results of a Prospective Multicenter Study

Background and Purpose— Early hemorrhagic transformation (HT) is a complication of ischemic stroke but its effect on patient outcome is unclear. The aims of this study were to assess: (1) the rate of early HT in patients admitted for ischemic stroke, (2) the correlation between early HT and functional outcome at 3 months, and (3) the risk factors for early HT. Methods— Consecutive patients with ischemic stroke were included in this prospective study in 4 study centers. Early HT was assessed by CT examination performed at day 5±2 after stroke onset. Study outcomes were 3-month mortality or disability. Disability was assessed using a modified Rankin score (≥3 indicating disabling stroke) by neurologists unaware of the occurrence of HT in the individual cases. Outcomes in patients with and without early HT were compared by &khgr;2 test. Multiple logistic regression analysis was used to identify predictors for HT. Results— Among 1125 consecutive patients (median age 76.00 years), 98 (8.7%) had HT, 62 (5.5%) had hemorrhagic infarction, and 36 (3.2%) parenchymal hematoma. At 3 months, 455 patients (40.7%) were disabled or died. Death or disability was seen in 33 patients with parenchymal hematoma (91.7%), in 35 patients with hemorrhagic infarction (57.4%) as compared with 387 of the 1021 patients without HT (37.9%). At logistic regression analysis, parenchymal hematoma, but not hemorrhagic infarction, was independently associated with an increased risk for death or disability (OR 15.29; 95% CI 2.35 to 99.35). At logistic regression analysis, parenchymal hematoma was predicted by large lesions (OR 12.20, 95% CI 5.58 to 26.67), stroke attributable to cardioembolism (OR 5.25; 95% CI 2.27 to 12.14) or to other causes (OR 6.77; 95% CI 1.75 to 26.18), high levels of blood glucose (OR 1.01; 95% CI 1.00 to 1.01), and thrombolytic treatment (OR 3.54, 95% CI 1.04 to 11.95). Conclusions— Early HT occurs in about 9% of patients. Parenchymal hematoma, seen in about 3% of patients, is associated with an adverse outcome. Parenchymal hematoma was predicted by large lesions attributable to cardioembolism or other causes, high blood glucose, and treatment with thrombolysis.

CSF phosphorylated tau is a possible marker for discriminating Alzheimer's disease from dementia with Lewy bodies. Phospho-Tau International Study Group.

Abstract Tau and β-amyloid (1–42) (Aβ42) are two independent markers for the early diagnosis of Alzheimers disease (AD). In the present study, biochemical markers were validated as tools for differential diagnosis between AD and dementia with Lewy bodies (DLB). Tau, Aβ42 and phosphotau (181P) were measured in cerebrospinal fluid (CSF) from controls (n=40) and from patients with AD (n=80) or DLB (n=43) using the HT7-AT270 assay (prototype version). In comparison with AD, in DLB no differences were found for Aβ42 and lower phospho-tau. ROC analysis was used to compare the discriminatory power of total tau with that of phospho-tau. The area under the curve (AUC) amounted to 0.782±0.048 (mean ±SE) for tau and to 0.839±0.042 for phospho-tau (p<0.039) for differentiation of AD from DLB. The present results indicate that CSF phospho-tau may be a good marker for differentiation between AD and DLB.

Cerebrospinal Fluid Biomarkers in Parkinson's Disease with Dementia and Dementia with Lewy Bodies

BACKGROUND Clinical criteria for differentiating Parkinsons disease (PD) with dementia (PDD) from dementia with Lewy bodies (DLB) are unsatisfactory. Their existence as distinct clinicopathologic entities is still debated, although the burden of Alzheimers disease (AD) pathology seems higher in DLB. Thus, analysis of cerebrospinal fluid (CSF) biomarkers (beta-amyloid(1-42) [Abeta42], total tau, and hyperphosphorylated tau [p-tau]) in living subjects might provide significant pathophysiological information on these diseases. METHODS Cerebrospinal fluid biomarkers were measured in DLB (n = 19), PDD (n = 18), and AD (n = 23) subjects matched for age, sex, and dementia severity, as well as in PD (n = 20) and normal control subjects (n = 20). RESULTS DLB showed the lowest mean CSF Abeta42 levels, with a negative association to dementia duration (rho = -.42, p = .07). In DLB patients, mean CSF total tau levels were significantly lower than in AD patients (508 +/- 387 vs. 960 +/- 619, respectively) but twofold to threefold higher than in PDD (286 +/- 184), PD (160 +/- 64), or normal control subjects (177 +/- 76), with a positive association to dementia severity (Mini-Mental State Examination: rho = -.54, p = .02; Milan Overall Dementia Assessment: rho = -.66, p = .002). PDD patients had mean CSF Abeta42 and total tau levels similar to those seen in PD patients. Hyperphosphorylated tau was significantly increased in the AD group only. CONCLUSIONS Cerebrospinal fluid Abeta42 and total tau have a different behavior in DLB and PDD, being related to duration and severity of dementia in DLB alone. Hyperphosphorylated tau is not significantly altered in these conditions.

Analytical performance and clinical utility of the INNOTEST (R) PHOSPHO-TAU((181P)) assay for discrimination between Alzheimer's disease and dementia with Lewy bodies

Abstract Background: Total tau (T-tau) and β-amyloid(1-42) (Aβ1-42) levels in cerebrospinal fluid (CSF) can differentiate Alzheimers disease (AD) from normal aging or depressive pseudo-dementia. Differential diagnosis from dementia with Lewy bodies (DLB) in clinical settings is difficult. Methods: The analytical performance of the INNOTEST® PHOSPHO-TAU(181P) assay was validated in terms of selectivity, sensitivity, specificity, precision, robustness, and stability. Clinical utility of the assay alone, or combined with T-tau and Aβ1-42, for discrimination of AD (n=94) from patients suffering from DLB (n=60) or from age-matched control subjects (CS) (n=60) was assessed in a multicenter study. Results: CSF concentrations of tau phosphorylated at threonine 181 (P-tau181P) in AD was significantly higher than in DLB and CS. Discriminant analysis, a classification tree, and logistic regression showed that P-tau181P was the most statistically significant single variable of the three biomarkers for discrimination between AD and DLB. Conclusions: P-tau181P quantification is a robust and reliable assay that may be useful in discriminating AD from DLB. Clin Chem Lab Med 2006;44:1472–80.

Neurotransmitter deficits in behavioural and psychological symptoms of Alzheimer's disease

Behavioural and psychological symptoms of dementia (BPSD) occur in 50-90% of Alzheimers disease (AD) patients. Imbalance of different neurotransmitters (acetylcholine, dopamine, noradrenaline and serotonin), involvement of specific brain regions responsible for emotional activities (parahippocampal gyrus, dorsal raphe and locus coeruleus) and cortical hypometabolism have been proposed as neurobiological substrate of BPSD. Compared to with respect to the neurochemical component, the cholinergic dysfunction seems to play a major role in contributing to BPSD occurrence. This view is also supported by the findings of recent trials with cholinesterase inhibitors, showing that these drugs are effective in controlling and/or improving BPSD, independent on effects on cognitive dysfunction. On the site of psychotropic drugs, atypical or novel antipsychotics represent the reference drugs for treating BPSD, whereas classic antipsychotic drugs for their profile and the potential side effects should be avoided.

Diagnosing prodromal Alzheimer's disease: role of CSF biochemical markers.

Mild cognitive impairment (MCI) is an aetiologically heterogeneous syndrome. A correct prediction of MCI conversion to Alzheimers disease (AD) represents a primary goal in routine clinical practice. Since the presence of pathological levels in >or=2 cerebrospinal fluid (CSF) biomarkers; amyloid protein (Abeta42), total tau (h-tau) and phospho-tau (p-tau) seems to reliably identifying MCI subjects converting to AD, we report our experience in a routine clinical setting. In the period from January 2001 to June 2003, 273 consecutive patients referred to our Memory Clinic for diagnostic assessment of cognitive impairment. Of them, 180 underwent a complete diagnostic evaluation including CSF dosage of fragment 1-42 of amyloid protein, total tau and phospho-tau (ELISA Method, Innogenetics, Gent, Belgium), after vascular or other secondary causes of dementia could be excluded. At baseline, 38% of the MCI subjects (20/55) showed pathological levels in >or=2 CSF biomarkers. After 1 year, 11 MCI patients converted to dementia, 33 remained stable, 11 showed a further progression of cognitive impairment still not fulfilling the diagnostic criteria for dementia. Of the 11 converters, 10 showed >or=2 pathological values CSF biomarkers and in all of them, p-tau was high. On the contrary, 29 out of 33 stable MCI (88%) showed no or one pathological CSF value. We confirm that pathological levels in >or=2 CSF biomarkers reliably predict MCI conversion to AD and correctly identify the stable form of MCI.

Nimodipine and Its Use in Cerebrovascular Disease: Evidence from Recent Preclinical and Controlled Clinical Studies

Nimodipine is a 1,4-dihydropyridine-derivative Ca2+-channel blocker developed approximately 30 years ago. It is highly lipophilic, crosses the blood-brain barrier, and reaches brain and cerebrospinal fluid. Early treatment with nimodipine reduces the severity of neurological deficits resulting from vasospasm in subarachnoid haemorrhage (SAH) patients. In SAH, nimodipine reduced spasm-related deficits of all severities, but no spasm-unrelated deficits. This paper has reviewed preclinical studies on the influence of nimodipine in various animal models of cerebral ischemia, with particular attention toward investigations published in the last 10 years. These studies further support the main indication of nimodipine, by clarifying some mechanisms of the anti-ischemic activity of the compound. Papers reporting a possible role of nimodipine in epileptogenesis were also examined. Clinical studies on nimodipine were grouped into subarachnoid hemorrhage, acute ischemic stroke, cerebral ischemia without stroke, dementia disorders, and migraine. Clinical investigations have shown that the drug improves neurological outcome by reducing the incidence and severity of ischemic deficits in patients with SAH from ruptured intracranial berry aneurysms regardless of their post-ictus neurological condition. No relevant effects of treatment with nimodipine were reported for acute ischemic stroke, cerebral ischemia without stroke, and migraine, except than for cluster headache. The less pronounced cardiovascular effects of nimodipine compared to other dihydropyridine-type Ca2+-channel blockers probably accounts for its use out of label for treating patients affected by chronic cerebral ischemia and vascular cognitive impairment. However, the blood pressure-lowering effects of nimodipine should not be minimized, as clinical studies have documented lowering blood pressure in small groups of patients, including cases of withdrawn due to pronounced hypotension induced by nimodipine administration. In the area of vascular cognitive impairment, short-term benefits of nimodipine do not justify its use as a long-term anti-dementia drug, and benefits obtained in elderly patients affected by subcortical vascular dementia require to be confirmed by other groups and in larger scale trials. In conclusion, nimodipine is a safe drug with an important place in pharmacotherapy and with the main documentation for reduction in the severity of neurological deficits resulting from vasospam in SAH patients.

Mild hyperhomocysteinemia is a risk-factor in all etiological subtypes of stroke.

Abstract.The role of hyperhomocysteinemia as independent risk factor for stroke needs to be confirmed. The aims of our study were to assess (i) the association between risk of stroke and increasing values of plasma homocysteine and (ii) the interaction between mild hyperhomocysteinemia and conventional vascular risk factors. We studied 161 consecutive patients with first-ever ischemic stroke classified using TOAST criteria and 152 neurologically healthy controls. Homocysteine was measured using high performance liquid chromatography (HPLC). Homocysteinemia was elevated in all stroke subtypes: 13.0±2.5 µmol/l in patients with cardioembolic disease, 13.9±5.4 µmol/l in those with small vessel diseases, 15.5±6.8 µmol/l in cases of undetermined stroke, and 17.8±13.5 µmol/l in patients with large vessel disease. Mean homocysteinemia was 8.10 µmol/l (SD=2.5) in controls. The logistic regression analysis showed that important independent risk factors for ischemic stroke were hypertension (p<0.0001; OR= 3.205; 95% CI, 1.788–5.742), hyperhomocysteinemia (p<0.0001; OR=1.425; 95% CI, 1.300–1562) and hyperlipidemia (p=0.018; OR=2.243; 95% CI, 1.147–4.385). Hyperhomocyst(e)inemia is an independent risk factor for all stroke subtypes and should be routinely measured and treated in stroke patients.

Acute Hyperglycemia and Early Hemorrhagic Transformation in Ischemic Stroke

Background: Hyperglycemia has been claimed to be associated with hemorrhagic transformation (HT) in patients with acute ischemic stroke treated with thrombolysis. The aim of this study was to assess whether the admission blood glucose level is related to HT in a prospective study in consecutive patients with acute ischemic stroke. Methods: Consecutive patients admitted for ischemic stroke to 4 Italian hospitals were included in this prospective cohort study. Results: Among 1,125 consecutive patients included in the analysis, 98 (8.7%) had HT: 62 (5.5%) had hemorrhagic infarction (HI) and 36 (3.2%) parenchymal hematoma (PH). A blood glucose level >110 mg/dl was found in 42.4% of the patients, a level between 110 and 149 mg/dl in 25.2%, and a level >150 mg/dl in 17.2%. At 3 months, 7 patients were lost at follow-up, 326 patients (29.2%) were disabled (modified Rankin score ≥3) and 129 died (11.5%). PH was associated with an increased risk of death or disability (OR 15.29, 95% CI 2.35–99.35). However, this was not the case for HT overall and HI. At logistic regression analysis, PH was predicted by high levels of admission blood glucose (OR 1.01, 95% CI 1.00–1.01 for 1 added mg/dl). The rate of PH was 2.1% in patients with <110 mg/dl, 3.6% in patients with a level between 110 and 149 mg/dl and 6.4% in patients with a level >150 mg/dl. The curve estimation regression model showed a significant linear increase in the risk of PH related to an increase in blood glucose levels (R2 = 0.007, p = 0.007). Conclusions: Hyperglycemia during acute ischemic stroke predisposes to PH, which in turn determines a nonfavorable outcome at 3 months. This relationship seems to be linear.

Treatment of Alzheimer's disease: From pharmacology to a better understanding of disease pathophysiology

Alzheimers disease (AD) is the most common cause of cognitive impairment in older patients and is expected to increase greatly in prevalence in the next future. It is characterized by the development of senile plaques and neurofibrillary tangles, which are associated with neuronal loss affecting to a greater extent cholinergic neurons. A cascade of pathophysiological events is triggered in AD that ultimately involves common cellular signalling pathways and leads to cellular and neural networks dysfunction, failure of neurotransmission, cell death and a common clinical outcome. The process is asynchronous and viable neurons remain an important target for therapeutic intervention at each stage of disease evolution. At present symptomatic drugs inhibiting the degradation of acetylcholine within synapses and more recently glutamate receptor antagonists represent the mainstay of therapy. However, interventions able to halt or slow disease progression (i.e., disease-modifying agents) are necessary. Although much progress has been made in this area, there are currently no clinically approved interventions for AD classed as disease modifying or neuroprotective. This paper reviews the main symptomatic strategies available for treating AD and future strategies for improving our therapeutic approach to AD.