Luigi Murri

Causative and susceptibility genes for Alzheimer's disease: a review.

Alzheimers disease (AD) is the most common type of dementia in the elderly population. Three genes have been identified as responsible for the rare early-onset familial form of the disease: the amyloid precursor protein (APP) gene, the presenilin 1 (PSEN1) gene and the presenilin 2 (PSEN2) gene. Mutations in these genes, however, account for less than 5% of the total number of AD cases. The remaining 95% of AD patients are mostly sporadic late-onset cases, with a complex aetiology due to interactions between environmental conditions and genetic features of the individual. In this paper, we review the most important genes supposed to be involved in the pathogenesis of AD, known as susceptibility genes, in an attempt to provide a comprehensive picture of what is known about the genetic mechanisms underlying the onset and progression of AD. Hypotheses about the role of each gene in the pathogenic pathway are discussed, taking into account the functions and molecular features, if known, of the coded protein. A major susceptibility gene, the apolipoprotein E (APOE) gene, found to be associated with sporadic late-onset AD cases and the only one, whose role in AD has been confirmed in numerous studies, will be included in a specific chapter. As the results reported by association studies are conflicting, we conclude that a better understanding of the complex aetiology that underlies AD may be achieved likely through a multidisciplinary approach that combines clinical and neurophysiological characterization of AD subtypes and in vivo functional brain imaging studies with molecular investigations of genetic components.

Cytochrome c oxidase and mitochondrial F1F0-ATPase (ATP synthase) activities in platelets and brain from patients with Alzheimer’s disease

Evidence suggests that mitochondrial dysfunction is prominent in Alzheimers disease (AD). A failure of one or more of the mitochondrial electron transport chain enzymes or of F(1)F(0)-ATPase (ATP synthase) could compromise brain energy stores, generate damaging reactive oxygen species (ROS), and lead to neuronal death. In the present study, cytochrome c oxidase (COX) and F(1)F(0)-ATPase activities of isolated mitochondria from platelets and postmortem motor cortex and hippocampus from AD patients and age-matched control subjects were assayed. Compared with controls, COX activity was decreased significantly in platelets (-30%, P < 0.01, n = 20) and hippocampus (-35 to -40%, P < 0.05, n = 6), but not in motor cortex from the AD patients. In contrast, in AD platelets and brain tissues, F(1)F(0)-ATP hydrolysis activity was not significantly changed. Moreover, the ATP synthesis rate was similar in mitochondria of platelets from AD patients and controls. These results demonstrate that COX but not F(1)F(0)-ATPase is a mitochondrial target in AD, in both a brain association area and in platelets. A reduced COX activity may make the tissue vulnerable to excitotoxicity or reduced oxygen availability.

Alteration of Cardiac Function in Patients with Temporal Lobe Epilepsy: Different Roles of EEG-ECG Monitoring and Spectral Analysis of RR Variability

Summary: Purpose: Because several reports have described the relation between epilepsy and cardiac arrhythmias and suggest that changes in autonomic neural control of the heart could be involved in the pathogenesis of sudden unexplained death in patients with epilepsy, the aim of this study was to evaluate cardiac function in patients with temporal lobe epilepsy.

Daytime sleepiness in mild and moderate Alzheimer's disease and its relationship with cognitive impairment

The increased tendency to fall asleep during the daytime together with increased wakefulness during the night has been demonstrated in patients with advanced Alzheimers disease (AD). The aim of this study was to assess daytime sleep propensity in a cohort of patients with mild/moderate AD and to correlate it with cognitive impairment. Twenty drug‐free AD patients meeting the NINCDS‐ADRDA criteria for probable AD were evaluated. According to their Clinical Dementia Rating scores, subjects were classified into mild (CDR1; n = 11) and moderate (CDR2; n = 9) dementia patients. A group of 12 healthy subjects was taken as controls. The subjects were evaluated by the multiple sleep latency test (MSLT) after their nocturnal sleep pattern had been assessed by a polysomnographic recording throughout the night before. Both groups of AD patients showed a higher level of daytime sleepiness, which was statistically significant for mean daytime sleep latency (MDSL) (controls versus CDR1 and versus CDR2, CDR1 versus CDR2) and for 10:00 and 12:00 hour naps (controls versus CDR1, controls versus CDR2). In the entire group of AD patients, MDSL was significantly related with MMSE, De Renzis Token test, verbal fluency, verbal digit span, story recall, Ravens Progressive Matrices, Weigl test and Bentons three‐dimensional test. These data indicate that an increased sleep propensity during daytime occurs also in patients with mild/moderate AD detected by objective neurophysiological techniques.

The role of norepinephrine in epilepsy: from the bench to the bedside.

This article provides a brief review of the role of norepinephrine (NE) in epilepsy, starting from early studies reproducing the kindling model in NE-lesioned rats, through the use of specific ligands for adrenergic receptors in experimental models of epilepsy, up to recent advances obtained by using transgenic and knock-out mice for specific genes expressed in the NE system. Data obtained from multiple experimental models converge to demonstrate the antiepileptic role of endogenous NE. This effect predominantly consists in counteracting the development of an epileptic circuit (such as in the kindling model) rather than increasing the epileptic threshold. This suggests that NE activity is critical in modifying epilepsy-induced neuronal changes especially on the limbic system. These data encompass from experimental models to clinical applications as recently evidenced by the need of an intact NE innervation for the antiepileptic mechanisms of vagal nerve stimulation (VNS) in patients suffering from refractory epilepsy. Finally, recent data demonstrate that NE loss increases neuronal damage following focally induced limbic status epilepticus, confirming a protective effect of brain NE, which has already been shown in other neurological disorders.

The prognostic value of evoked responses from primary somatosensory and auditory cortex in comatose patients

OBJECTIVE To evaluate somatosensory and auditory primary cortices using somatosensory evoked potentials (SEPs) and middle latency auditory evoked potentials (MLAEPs) in the prognosis of return to consciousness in comatose patients. METHODS SEPs and MLAEPs were recorded in 131 severe comatose patients. Latencies and amplitudes were measured. Coma had been caused by transient cardiac arrest (n=49), traumatic brain injury (n=22), stroke (n=45), complications of neurosurgery (n=12) and encephalitis (n=3). One month after the onset of coma patients were classified as awake, still comatose or dead. Three months after (M3), they were classified into one of the 5 categories of the Glasgow outcome scale (GOS). RESULTS At M3, 41.2% were dead, 47.3% were conscious (GOS 3-5) and 11.5% had not recovered consciousness. None of the patients in whom somatosensory N20 and auditory Pa were absent did return to consciousness and in the post-anoxic group, reduced cortical amplitude too was always associated with bad outcome. Conversely, N20 and Pa were present, respectively, in 33/69 and 34/69 patients who did not recover. CONCLUSIONS The prognostic value of SEPs and MLAEPs in comatose patients depends on the cause of coma. Measurement of response amplitudes is informative. Abolition of cortical SEPs and/or cortical MLAEPs precludes post-anoxic comatose patients from returning to consciousness (100% specificity). In any case, the presence of short latency cortical somatosensory or auditory components is not a guarantee for return to consciousness. Late components should then be recorded.

Paroxetine in Parkinson’s disease: Effects on motor and depressive symptoms

Article abstract Selective serotonin reuptake inhibitors have been used in the treatment of depression in patients with PD. Conflicting data as to whether selective serotonin reuptake inhibitors worsen parkinsonian motor symptomatology have been reported. In this study, the additional 6 months therapy with paroxetine 20 mg/d in a group of depressed patients with PD did not modify parkinsonian motor function (Unified Parkinson’s Disease Rating Scale scores); however, in one patient, fully reversible worsening of tremor was observed. Depression, as evaluated by Beck Depression Inventory and Hamilton Depression Rating Scale, improved from baseline to final visit (p < 0.05 by analysis of variance).

Citalopram as treatment of depression in patients with epilepsy.

Objectives:To assess the safety of citalopram as a treatment of depression in patients with epilepsy. Methods:This is an open, multicentered, uncontrolled study. Depressed epileptic patients on antiepileptic drugs (AEDs) took part in the study. Patients who had a mild frequency of seizures in the 4 previous months underwent treatment with citalopram (20 mg/d) for 4 consecutive months. A change in seizure frequency from the baseline was chosen as the primary measure for the safety of citalopram and efficacy against depressive symptoms was taken as secondary measure. Depression was rated using the Montgomery–Åsberg and Zung depression rating scales. Clinical assessments were performed at baseline, and at 2 and 4 months of citalopram therapy. Results:Forty-five patients were enrolled. Six patients dropped out of the study early: none of them because of a deterioration of seizure frequency. An overall improvement in seizure frequency was observed in the 39 patients who completed the study. Plasma AED concentrations were unchanged during therapy, and depressive symptoms improved markedly. Twenty-two patients complained of adverse effects, mainly headache, nausea, dizziness, somnolence, and fatigue. Conclusions:In this open, multicentered, uncontrolled study, 4 months’ of treatment with citalopram (20 mg/d) were associated with an improvement in depressive symptoms and reduction in seizure frequency.

Dopaminergic modulation of visual-spatial working memory in Parkinson's disease

Visual-spatial working memory (WM) impairment is frequently associated with the early stage of Parkinson’s disease (PD). The aim of this study was to evaluate the performance of a group of PD patients in visual-spatial and visual-object WM tasks and to investigate the effect of administering the dopaminergic agonist apomorphine (experiment 1) or the dopamine precursor L-dopa (experiment 2) on the performance of tests assessing these functions. To study WM processes, the PD patients and age-matched normal controls were given an n-back task paradigm. In both experiments, the PD patients were submitted to two evaluations: one after a 12-hour therapy washout and the other 15 min after a subcutaneous infusion of apomorphine (average 0.04 mg/kg) or 20/30 min after L-dopa intake (200 mg p.o.). The apomorphine infusion had a worsening effect on reaction times in both visual-spatial and visual-object WM tasks, but it did not influence performance accuracy. Instead, L-dopa administration had a ameliorative effect on accuracy and reaction times in both visual-spatial and visual-object tasks. These results highlight the role of dopamine in the modulation of the WM function in PD patients.

Prevalence of Sleep Disturbances in Mild Cognitive Impairment and Dementing Disorders: A Multicenter Italian Clinical Cross-Sectional Study on 431 Patients

Background/Aims: Sleep disturbances are common in the elderly and in persons with cognitive decline. The aim of this study was to describe frequency and characteristics of insomnia, excessive daytime sleepiness, sleep-disordered breathing, REM behavior disorder and restless legs syndrome in a large cohort of persons with mild cognitive impairment or dementia. Methods: 431 consecutive patients were enrolled in 10 Italian neurological centers: 204 had Alzheimer’s disease, 138 mild cognitive impairment, 43 vascular dementia, 25 frontotemporal dementia and 21 Lewy body dementia or Parkinson’s disease dementia. Sleep disorders were investigated with a battery of standardized questions and questionnaires. Results: Over 60% of persons had one or more sleep disturbances almost invariably associated one to another without any evident and specific pattern of co-occurrence. Persons with Alzheimer’s disease and those with mild cognitive impairment had the same frequency of any sleep disorder. Sleep-disordered breathing was more frequent in vascular dementia. REM behavior disorder was more represented in Lewy body or Parkinson’s disease dementia. Conclusion: A careful clinical evaluation of sleep disorders should be performed routinely in the clinical setting of persons with cognitive decline. Instrumental supports should be used only in selected patients.