Biomedical subjects

Lucilla Parnetti

Publications and source records attributed to Lucilla Parnetti.

At least 19 recordsLinked to original sources

PubMed2026

APOE-stratified genome-wide association analyses provide insights into the genetic etiology of Alzheimers's disease.

Among the more than 90 identified genetic risk loci for late-onset Alzheimer's disease (AD) and related dementias, the apolipoprotein E (APOE) gene ɛ2/ɛ3/ɛ4 polymorphisms remain the longstanding benchmark for genetic disease risk with a consistently large effect across studies1-10. Despite this massive signal, the exact mechanisms by which ɛ4 increases and ɛ2 decreases dementia risk remain poorly understood. Notably, recent trials of anti-amyloid therapies suggest less efficacy and higher risks of severe side effects in ε4 carriers11-13, hampering the treatment of those with the highest unmet need. To improve our understanding of the genetic architecture of AD in the context of its main genetic driver, we performed genome-wide association studies (GWASs) stratified by ε4 and ε2 carrier status. HP1BP3, SLC50A1, PTPRC, NPAS3, DDHD1, CHST9, SMYD2, PRAMEF1 and GFRA1 emerged as new genomic signals for AD risk, appearing only when stratified by APOE carrier status. DDHD1 appeared especially promising, showing protective effects in ε4 carriers, being identified as an expression quantitative trait locus and being involved in rare neuronal diseases. Such APOE-stratified insights may help understand and overcome side effects, inform clinical trial enrollment strategies, and create the scientific basis for targeted, mechanism-driven therapies in neurodegenerative diseases.

Journal Article↗

PubMed2006

Effect of treatment with choline alphoscerate on hippocampus microanatomy and glial reaction in spontaneously hypertensive rats.

The influence of long term treatment with choline alphoscerate on microanatomy of hippocampus and glial reaction was assessed in spontaneously hypertensive rats (SHR) used as an animal model of cerebrovascular disease. Choline alphoscerate is a cholinergic precursor, which has shown to be effective in countering cognitive symptoms in forms of dementia disorders of degenerative, vascular or combined origin. Male spontaneously hypertensive rats (SHR) aged 6 months and age-matched normotensive Wistar-Kyoto (WKY) rats were treated for 8 weeks with an oral daily dose of 100 mg/kg of choline alphoscerate, 285 mg/kg of phosphatidylcholine (lecithin) or vehicle. On the hippocampus of different animal groups, nerve cell number and GFAP-immunoreactive astrocytes were assessed by neuroanatomical, immunochemical and immunohistochemical techniques associated with quantitative analysis. Treatment with choline alphoscerate countered nerve cell loss and glial reaction primarily in the CA1 subfields and in the dentate gyrus of the hippocampus of SHR. Phosphatidylcholine did not affect hypertension-dependent changes in hippocampal microanatomy. Both compounds did not affect blood pressure values in SHR. These data suggest that choline alphoscerate may play a role in the countering hippocampal changes induced by cerebrovascular involvement. The observation that treatment with choline alphoscerate attenuates the extent of glial reaction in the hippocampus of SHR suggests also that the compound may afford neuroprotection in this animal model of vascular brain damage.

Analysis of Variance↗

PubMed2006

Pathways of neurodegeneration and experimental models of basal ganglia disorders: downstream effects of mitochondrial inhibition.

The basal ganglia circuit plays a key role in the regulation of voluntary movements as well as in behavioural control and cognitive functions. The main pathogenic role of mitochondrial dysfunctions is now accepted in the neurodegenerative process and the mitochondria have been successfully used as subcellular targets to obtain relevant experimental models of basal ganglia neurodegenerative disorders. Mitochondrial toxins act through an inhibition of the respiratory chain complexes. These toxins, by uncoupling cellular respiration, shift the cell into a state of oxidative stress and trigger several bidirectional links with the excitotoxic process. Moreover, the in vitro inhibition of the respiratory chain complexes alters the electrophysiological properties of the neurons. The downstream effects triggered by mitochondrial complexes inhibition provide a model integrating genetic and environmental pathogenic factors to explain the selective neuronal vulnerability.

Animals↗

PubMed2006

Influence of dementia on antithrombotic therapy prescribed before stroke in patients with atrial fibrillation.

BACKGROUND AND PURPOSE: Oral anticoagulation (OAC) decreases the risk of stroke in patients with nonvalvular atrial fibrillation (NVAF), but remains underused in practice. The aim of this study was to test the hypothesis that prestroke dementia influenced the nonprescription of OAC before stroke. METHODS: This is an ancillary study of Stroke in Atrial Fibrillation Ensemble II, an observational study conducted in patients with a previously known NVAF, consecutively admitted for an acute stroke to French and Italian centers. Prestroke dementia was evaluated by the clinical physician and validated by an Informant Questionnaire for Cognitive Decline in the Elderly score of >or=104 in patients with a reliable informant. RESULTS: Of 204 patients, 24 patients met criteria for prestroke dementia according to GP's opinion. The only variables independently associated with OAC before stroke were follow-up by a cardiologist (adjusted OR: 3.33; 95% CI: 1.47-7.53) and a younger age of patients (adjusted OR: 0.94; 95% CI: 0.89-0.99). Variables independently associated with any antithrombotic drug therapy before stroke were follow-up by a general practitioner (adjusted OR: 2.78; 95% CI: 1.09-7.11), and by a cardiologist (adjusted OR: 3.15; 95% CI: 1.48-6.69). CONCLUSION: In daily practice, the under-prescription of OAC in patients with NVAF mainly depends on co-morbidity and on characteristics of the physician, not on prestroke dementia.

Administration, Oral↗

PubMed2006

Secondary prevention of stroke in patients with atrial fibrillation: factors influencing the prescription of oral anticoagulation at discharge.

BACKGROUND: Oral anticoagulation (OAC) is the only treatment that has shown a significant benefit to reduce the risk of recurrence in patients with ischemic stroke and nonvalvular atrial fibrillation (NVAF). However, OAC is still underused, even at discharge from neurological centers. The objective of this study was to identify the reasons underlying the prescription of OAC at discharge after an ischemic stroke in patients with NVAF. METHODS: We investigated the reasons why ischemic stroke patients with NVAF were not treated with OAC at discharge from 40 centers located in 5 European countries (Austria, Belgium, France, Italy, and Portugal). RESULTS: Of 320 ischemic stroke survivors at discharge, 186 (58.1%) received OAC, while 260 (81.3%) patients were theoretically eligible according to guidelines and the absence of contraindications. There were significant differences between countries and the logistic regression analysis found being already under OAC before stroke, having no leukoaraiosis, having no potential contraindication, being younger than 75 years, being married and suffering from angina pectoris as independent predictors of being discharged under OAC. CONCLUSION: This study suggests that besides patient-related factors, the prescription of OAC is also significantly influenced by the social environment and national practices.

Administration, Oral↗

PubMed2006

A convergent model for cognitive dysfunctions in Parkinson's disease: the critical dopamine-acetylcholine synaptic balance.

Parkinson's disease is classically characterised as a motor neurodegenerative disorder. Motor symptoms in the disorder are secondary to an altered dopamine-acetylcholine balance due to reduced striatal dopaminergic tone and subsequent cholinergic overactivity. In the past, anticholinergic drugs were given to improve motor aspects of the disease. There is now an increasing interest in the cognitive and non-motor symptoms of Parkinson's disease and in cholinesterase-inhibitor therapy for dementia associated with Parkinson's disease. In this Personal View, we reconsider the dopamine-acetylcholine balance theory and look at recent clinical findings and the possible cooperative role of dopamine and acetylcholine in the induction and maintenance of the long-lasting changes of striatal and cortical synaptic plasticity. We also discuss a convergent versus parallel model to explain cognitive dysfunctions in Parkinson's disease according to dopamine-acetylcholine dependent alterations in synaptic plasticity.

Acetylcholine↗

PubMed2006

Analytical performance and clinical utility of the INNOTEST PHOSPHO-TAU181P assay for discrimination between Alzheimer's disease and dementia with Lewy bodies.

BACKGROUND: Total tau (T-tau) and beta-amyloid((1-42)) (Abeta(1-42)) levels in cerebrospinal fluid (CSF) can differentiate Alzheimer's 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 Abeta(1-42), 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-tau(181P)) in AD was significantly higher than in DLB and CS. Discriminant analysis, a classification tree, and logistic regression showed that P-tau(181P) was the most statistically significant single variable of the three biomarkers for discrimination between AD and DLB. CONCLUSIONS: P-tau(181P) quantification is a robust and reliable assay that may be useful in discriminating AD from DLB.

Aged↗

PubMed2005

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

Behavioural and psychological symptoms of dementia (BPSD) occur in 50-90% of Alzheimer's 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.

Alzheimer Disease↗

PubMed2005

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

Alzheimer's 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.

Acetylcholine↗

PubMed2005

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 Alzheimer's 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.

Alzheimer Disease↗

PubMed2004

Dysphagia following Stroke.

BACKGROUND: Dysphagia is common after stroke. We aimed to study the prognosis of dysphagia (assessed clinically) over the first 3 months after acute stroke and to determine whether specific neurovascular-anatomical sites were associated with swallowing dysfunction. METHODS: We prospectively examined consecutive patients with acute first-ever stroke. The assessment of dysphagia was made using standardized clinical methods. The arterial territories involved were determined on CT/MRI. All patients were followed up for 3 months. RESULTS: 34.7% of 406 patients had dysphagia. Dysphagia was more frequent in patients with hemorrhagic stroke (31/63 vs. 110/343; p = 0.01). In patients with ischemic stroke, the involvement of the arterial territory of the total middle cerebral artery was more frequently associated with dysphagia (28.2 vs. 2.2%; p < 0.0001). Multivariate analysis revealed that stroke mortality and disability were independently associated with dysphagia (p < 0.0001). CONCLUSIONS: The frequency of dysphagia was relatively high. Regarding anatomical-clinical correlation, the most important factor was the size rather than the location of the lesion. Dysphagia assessed clinically was a significant variable predicting death and disability at 90 days.

Aged↗

PubMed2004

Stroke prevention and atrial fibrillation: reasons leading to an inappropriate management. Main results of the SAFE II study.

AIMS: The aim of the Stroke and Atrial Fibrillation Ensemble (SAFE) II study was to identify the reasons underlying the under-utilization of oral anticoagulation (OAC) in patients with nonvalvular atrial fibrillation (NVAF). METHODS: We investigated from all available sources the reasons why patients hospitalized for a stroke, who had a previously known NVAF, were not receiving OAC beforehand. We interviewed general practitioners (GPs) and cardiologists with a structured questionnaire, to identify the reasons for their therapeutic choice. RESULTS: Of 370 patients, 257 were theoretically eligible for OAC according to guidelines and the presence of contra-indications, but only 82 (22.2%) of them had actually received OAC before. We found that factors independently associated with the prescription of OAC were being followed-up by a cardiologist and having a younger GP. The leading reason evoked by GPs or cardiologists to explain why patients were not treated with OAC was the presence of a 'potential contra-indication', which was often inappropriate, followed by 'there was no indication', 'low compliance' and 'fear of bleeding'. CONCLUSIONS: An important reason for not prescribing OAC was the lack of knowledge about trials and guidelines. Medical education about OAC in NVAF should therefore be improved.

Aged↗

PubMed2003

Recanalization of cervical artery dissection: influencing factors and role in neurological outcome.

BACKGROUND AND PURPOSE: Generally, the prognosis for cervical artery dissection (CAD) is uncertain. The recanalization rate of CAD can be up to 85% within 3 months. This study evaluates the variables that might affect recanalization and the role of recanalization as a predictor for neurological outcome. PATIENTS AND RESULTS: This study prospectively included 38 patients with acute stroke following occlusion due to CAD (18 males, 20 females, median age 50.5 years, range 16-82). Vertebral and carotid dissections were equally distributed (19 carotid dissections). The recanalization rate was influenced by the presence of hypertension (p = 0.001). Outcomes were dependent on infarct location. Patients with lateral medullary infarction returned to functional independence (p = 0.026), while patients with deep hemispheric infarction tended to have a disabling stroke (p = 0.068). The presence of good collaterals seemed to influence functional independence (p = 0.03). CONCLUSION: There seemed to be no relationship between outcome and the rate of recanalization following CAD. Recanalization appeared to be a spontaneous mechanism, which could have depended on the intrinsic condition of the vessels. Finally, neurological outcome was dependent on lesion localization and the presence of good collaterals.

Acute Disease↗

PubMed2003

Selection of thrombogenetic antiphospholipid antibodies in cerebrovascular disease patients.

BACKGROUND AND PURPOSE: The association between anticardiolipin antibodies (aCL) and thrombosis is well recognized, but its role as an independent risk factor for stroke is not. The study's aim was to investigate the presence of antiphospholipid antibodies (aPL) and ischemic vascular events by using both traditional means the estimation of aCL and glycoprotein (beta(2)GP1) antibodies. Additionally both aCL/beta(2)GP1 and aPLmix/beta(2)GP1 antibodies were measured. The measurement of these two antibodies was determined by using as target antigens, either cardiolipin alone or a mixture of different phospholipids coated with human beta(2)GP1 in order to select only the autoimmune antibodies. One hundred and twenty-two consecutive patients with first-ever acute ischemic cerebrovascular event were included and compared with controls. The presence of aCl in patients (20.5 %) and controls (14.7 %) was not significantly different (p = 0.1). The presence of abeta(2)GP1 (6.5 % versus 4.9 %, p = 0.7) was also not significant, while there were associations for aCL/b2GP1 13.9 % versus 4.9 % (p = 0.02) and aPLmix/beta(2)GP1 15.6 % versus 4.9 % (p = 0.01). These latter tests seem to be useful in assessing the autoimmune and therefore the thrombogenetic antibodies.

Adult↗

PubMed2003

Is ultrasound examination sufficient in the evaluation of patients with internal carotid artery severe stenosis or occlusion?

BACKGROUND AND PURPOSE: Carotid endarterectomy (CE) has been shown to be beneficial in patients with symptomatic high-grade internal carotid artery (ICA) stenosis. Some authors have suggested that when ultrasound shows a stenosis 70-99%, CE can be performed without further imaging study. However, ultrasound findings that suggest an ICA occlusion, not confirmed by angiography but which instead show a near-occlusion usually benefit from CE. The objectives of this study are: (1). to evaluate how angiography-obtained information on intracranial arteries affects the treatment decision in patients with 70-99% ICA stenosis, and (2). to evaluate when a symptomatic ICA occlusion shown by ultrasound could actually be a patent artery and therefore benefit from CE. MATERIALS AND METHODS: We prospectively collected the cerebral angiograms of 133 consecutive patients with TIA or non-disabling stroke due to large artery disease where ultrasound suggested a stenosis >or=70% or occlusion of symptomatic ICA; we calculated the frequency of intracranial vascular malformations and intracranial artery disease (IAD) located in the infraclinoid or supraclinoid portion of the ICA, and in the anterior or middle cerebral artery. RESULTS: Ultrasound showed 31 ICA occlusions and 102 ICA with 70-99% stenosis. All the patients with an ICA stenosis 70-99% on ultrasound examination had the degree of stenosis confirmed by angiography. Two out of 31 patients did not have a complete occlusion but angiography showed a near-occlusion and consequently they underwent CE. Sixty-five (62.5%) out of 104 patients with patent ICA had IAD (mild 26.9%, moderate 21.2%, and severe 14.4%). Five patients (4.8%) had intracranial vascular malformations (4 aneurysms and 1 arteriovenous malformation). One patient had disabling stroke during angiography. Seven patients (6.7%) did not undergo CE after angiography (1 patient had an aneurysm >10 mm, 1 patient had a very tight stenosis of the basilar artery, 5 patients had intracranial stenosis more severe than the extracranial stenosis). CONCLUSIONS: In patients that on the basis of ultrasound examination can benefit from CE, information on intracranial arteries is necessary. Moreover, complete occlusion cannot be detected with certainty only by ultrasound examination.

Aged↗

PubMedDate not supplied

Risk factors and stroke subtypes: results of five consecutive years of the Perugia Stroke Registry.

To understand the etiopathogenetic mechanisms of stroke and to target prevention, we need to know how risk factors differ among etiological subtypes. Our aims were to determine the different profile of risk factors for ischemic and hemorrhagic stroke subtypes in our cohort from the Perugia Hospital-Based Stroke Registry. We analyzed the characteristics and the different risk factors of 2,395 first-ever consecutive stroke patients admitted to the Perugia Hospitals in the period between January 1, 1998 and December 31, 2002. The prevalence of cerebrovascular risk factors in each stroke subtype was analyzed independently and compared with other subtypes of stroke pooled together by means of univariate analysis and logistic regression models. Hypertension occurred in 61% of patients; familial history of stroke in 41.6%; vascular disease in 27.2%; embolic heart disease in 22.3%; cigarette smoking in 21.6%. Different potentially modifiable risk factors profiles were identified for each ischemic subtype of stroke, while in hemorrhagic lobar stroke subtypes, only male gender was an independent risk factor.

Adult↗

PubMedDate not supplied

First-ever stroke and outcome in patients admitted to Perugia Stroke Unit: predictors for death, dependency, and recurrence of stroke within the first three months.

Predictors of poor outcome after first-ever stroke within 3 months in consecutive patients admitted to our Stroke Unit were defined. Factors included age, sex, risk factors, occurrence of transient ischemic attacks, extension of cerebral infarction, presumed cause of stroke, clinical findings, and demographic characteristics. Multiple regression models were used to analyze predictors of mortality, dependency and stroke recurrence. A total of 435 patients with first-ever stroke were included. Of these, 358 patients had ischemic stroke and 77 hemorrhagic stroke. Three-month mortality rate was 20.5%. After the same period, 24.6% of survivors were dependent (mRS > or = 3) and 5.0% of patients had recurrent stroke. Age, the presence of atrial fibrillation, impaired consciousness on admission, and stroke severity were related to mortality. The presence of stroke due to an undetermined cause or small vessel disease was associated with lower mortality. Partial anterior circulation syndrome or lacunar syndrome were both related to better outcome. The best predictors for dependency after 3 months were age and stroke severity. The only variable identified as the best predictor for recurrence was the presence of diabetes mellitus.

Age Factors↗

PubMedDate not supplied

Arterial hypertension and stroke prevention: an update.

High blood pressure (BP) is the most important modifiable risk factor for stroke and other vascular diseases. Evidence from randomized controlled trials supports the use of antihypertensive drugs to lower blood pressure for stroke prevention. There is some evidence that specific classes of antihypertensive drugs have different effects and/or their pharmacological actions differ in patient subgroups. This review evaluates the development of antihypertensive therapies and the latest studies of arterial hypertension and stroke prevention: HOPE trial (ramipril versus placebo), ALLHAT trial (CCB or/ and Angiotensin-Conventing enzyme Inhibitors (ACE-Is) versus diuretic), LIFE trial (losartan versus atenolol), and PROGRESS trial (perindopril or/and indapamide versus placebo). Despite the results of these relevant clinical trails, some aspects still remain unresolved. Future clinical trials on hypertension and stroke prevention should answer the following questions: Does lowering BP reduce stroke risk due to specific drug effect or class effect? Are angiotensin II receptor blockers (ARBs) better than ACE-Is? Should ACE-Is and ARBs be considered routinely for either high-risk stroke patients or patients with history of stroke or transient ischemic attack, irrespective of blood pressure? What is the role of lifestyle in BP control?

Antihypertensive Agents↗