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Publications and source records attributed to M Emre.
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The aim of this international guideline on dementia was to present a peer-reviewed evidence-based statement for the guidance of practice for clinical neurologists, geriatricians, psychiatrists, and other specialist physicians responsible for the care of patients with dementia. It covers major aspects of diagnostic evaluation and treatment, with particular emphasis on the type of patient often referred to the specialist physician. The main focus is Alzheimer's disease, but many of the recommendations apply to dementia disorders in general. The task force working group considered and classified evidence from original research reports, meta-analysis, and systematic reviews, published before January 2006. The evidence was classified and consensus recommendations graded according to the EFNS guidance. Where there was a lack of evidence, but clear consensus, good practice points were provided. The recommendations for clinical diagnosis, blood tests, neuroimaging, electroencephalography (EEG), cerebrospinal fluid (CSF) analysis, genetic testing, tissue biopsy, disclosure of diagnosis, treatment of Alzheimer's disease, and counselling and support for caregivers were all revised when compared with the previous EFNS guideline. New recommendations were added for the treatment of vascular dementia, Parkinson's disease dementia, and dementia with Lewy bodies, for monitoring treatment, for treatment of behavioural and psychological symptoms in dementia, and for legal issues. The specialist physician plays an important role together with primary care physicians in the multidisciplinary dementia teams, which have been established throughout Europe. This guideline may contribute to the definition of the role of the specialist physician in providing dementia health care.
BACKGROUND: The aim of this study was to evaluate the characteristic features of the mechanical responses and membrane potential changes induced by remifentanil in human umbilical arteries (HUAs). The ionic mechanisms underlying the electrophysiological responses were pharmacologically assessed using two K(+) channel blockers. METHODS: Thirty-eight HUAs were obtained. Contraction-relaxation, membrane potential changes and electrical responses of the HUAs were recorded. RESULTS: Remifentanil produced concentration-dependent relaxation in both endothelium-intact and endothelium-denuded HUA rings. Remifentanil produced a significantly greater relaxation response in intact than in denuded HUA rings. In endothelium-intact rings, pre-treatment with L-nitroarginine [N(w)-NITRO-(L)-ARGININE (L-NO-ARG)] or indomethacin decreased the degree of remifentanil-induced relaxation. Remifentanil (10(-9)-10(-6) mol/l) produced a transient concentration-dependent membrane hyperpolarization, which was not decreased by pre-treatment with L-NO-ARG or indomethacin. It also produced a small concentration-dependent hyperpolarization in the presence of charybdotoxin or tetraethylammonium. CONCLUSION: In both endothelium-intact and endothelium-denuded HUAs, remifentanil induces concentration-dependent vasorelaxation and simultaneously releases nitric oxide, prostaglandins and possibly an endothelium-derived hyperpolarizing factor. In addition, it produces hyperpolarization in a dose-dependent manner. Hyperpolarization induced by remifentanil involves the activation of Ca(2+)-dependent and Ca(2+)-independent potassium channels regulated by intracellular Ca(2+).
OBJECTIVE: To explore the profile of neuropsychiatric symptoms in patients with dementia associated with Parkinson's disease (PDD). METHODS: 537 patients with PDD drawn from an international multicentre clinical trial of rivastigmine were assessed using the 10-item Neuropsychiatric Inventory (NPI). A cluster analysis was used to investigate the inter-relationship of NPI items. Associations between the clusters and demographic and clinical variables were analysed. RESULTS: 89% of the patients presented at least one symptom on the NPI, 77% had two or more symptoms and 64% had at least one symptom with a score > or = 4. The most common symptoms were depression (58%), apathy (54%), anxiety (49%) and hallucinations (44%). Patients with more severe dementia and advanced Parkinson's disease had more neuropsychiatric symptoms. Nearly 60% of the care givers reported at least one NPI symptom to be of at least moderate severe distress. Five NPI clusters were identified: one group with few and mild symptoms (52%); a mood cluster (11%, high scores on depression, anxiety and apathy); apathy (24%; high apathy and low scores on other items); agitation (5%, high score on agitation and high total NPI score); and a psychosis cluster (8%; high scores on delusions and hallucinations). The psychosis and agitation clusters had the lowest Mini-Mental State Examination score and the highest Unified Parkinson's Disease Rating Scale and care giver distress scores. CONCLUSION: Neuropsychiatric symptoms are common in patients with PDD. The profile of these symptoms differs from that in other types of dementia. Subgroups with different neuropsychiatric profiles were identified. These subgroups may be associated with distinct neurobiological changes, which should be explored in future studies.
OBJECTIVE: To investigate the effects of attentional deficits on activities of daily living (ADL) in patients with dementia associated with Parkinson's disease (PDD). METHOD: 461 patients were assessed neuropsychologically. Factor analyses were used to differentiate attention from other cognitive functions and to differentiate different aspects of ADL functions. The effects of the attentional measure on ADL were examined using sequential multiple regression, controlling for age, sex, education, severity of motor symptoms and other cognitive functions. RESULTS: Three cognitive factors were identified, with one factor emerging as a measure of vigilance and focused attention. This factor predicted different aspects of ADL status even after controlling for motor functions and other cognitive factors. The attention factor was the single strongest cognitive predictor of ADL status, matching the strength of the effects of motor functions on ADL status. CONCLUSION: Impaired attention is an important determinant of ADL functions in patients with PDD.
In a 24-week, randomized, double-blind, placebo-controlled, multicenter study of rivastigmine, 487 patients with dementia associated with Parkinson disease underwent assessment of attention on the Cognitive Drug Research computerized cognitive assessment system before dosing and 16 and 24 weeks later. Significant benefits of rivastigmine over placebo were seen on all aspects of attention assessed: sustained attention, focused attention, consistence of responding, and central processing speed.
Parkin is known to be present in human neurons and peripheral nerves. Using an antibody against parkin protein we have now demonstrated that parkin is also expressed in the sarcoplasm and sarcolemmal region of human skeletal muscle fibres. We have also found different age-related patterns of expression with increase in intensity and organization of distribution at older ages. These findings suggest a change in the functional role of parkin in skeletal muscle with ageing and may contribute to understanding the mechanisms of muscle aging.
The dementia with Lewy bodies (DLB) Consortium has revised criteria for the clinical and pathologic diagnosis of DLB incorporating new information about the core clinical features and suggesting improved methods to assess them. REM sleep behavior disorder, severe neuroleptic sensitivity, and reduced striatal dopamine transporter activity on functional neuroimaging are given greater diagnostic weighting as features suggestive of a DLB diagnosis. The 1-year rule distinguishing between DLB and Parkinson disease with dementia may be difficult to apply in clinical settings and in such cases the term most appropriate to each individual patient should be used. Generic terms such as Lewy body (LB) disease are often helpful. The authors propose a new scheme for the pathologic assessment of LBs and Lewy neurites (LN) using alpha-synuclein immunohistochemistry and semiquantitative grading of lesion density, with the pattern of regional involvement being more important than total LB count. The new criteria take into account both Lewy-related and Alzheimer disease (AD)-type pathology to allocate a probability that these are associated with the clinical DLB syndrome. Finally, the authors suggest patient management guidelines including the need for accurate diagnosis, a target symptom approach, and use of appropriate outcome measures. There is limited evidence about specific interventions but available data suggest only a partial response of motor symptoms to levodopa: severe sensitivity to typical and atypical antipsychotics in approximately 50%, and improvements in attention, visual hallucinations, and sleep disorders with cholinesterase inhibitors.
AIM: To compare the plasma levels of endothelin-1 (ET-1) between patients with primary open angle glaucoma with visual field progression despite normal or normalised intraocular pressure and patients with stabile visual fields in a retrospective study. METHODS: The progressive group consisted of 16 primary open angle glaucoma patients and the group with stable visual field consisted of 15 patients. After a 30 minute rest in a supine position, venous blood was obtained for ET-1 dosing. Difference in the plasma level of ET-1 between two groups was compared by means of analysis of covariance (ANCOVA), including age, sex, and mean arterial blood pressure as covariates. RESULTS: ET-1 plasma levels were found to be significantly increased in patients with deteriorating (3.47 (SD 0.75) pg/ml) glaucoma when compared to those with stable (2.59 (SD 0.54) pg/ml) visual fields (p = 0.0007). CONCLUSIONS: Glaucoma patients with visual field progression in spite of normal or normalised intraocular pressure have been found to have increased plasma endothelin-1 levels. It remains to be determined if this is a secondary phenomenon or whether it may have a role in the progression of glaucomatous damage.
Absence of parkin has been shown to cause the downturned wing phenotype and severe disruption of myofibrils and mitochondrial abnormalities in parkin null mutant drosophila. The present report refers to studies on 3 patients with autosomal recessive Parkinson's disease with mild histopathological changes in muscle and a 'G' deletion at the exon9/intron9 junction or exon 3 deletion in the parkin gene. Using an antibody against a peptide corresponding to sequence number 305-323 of the human parkin protein it was demonstrated that parkin was expressed in skeletal muscle of these patients and that its distribution was similar to that in normal muscles. The mild nature of the histopathological changes, especially in the young patients, in the presence of parkin mutations may be due to residual E3-ubiquitin ligase activity of the mutant protein, to existence of muscle-specific splice-variants or to the relative functional insignificance of parkin in human muscle fibres. Further investigation of parkin expression in skeletal muscle is warranted.
AIMS: To investigate the source of ocular blood flow alterations in glaucoma. METHODS: In 56 patients with open angle glaucoma, blood flow parameters were obtained from both eyes in the ophthalmic and central retinal artery by means of colour Doppler imaging, as well as in the choroidal circulation and the neuroretinal rim of the optic nerve by means of laser Doppler flowmetry. Based on these haemodynamic parameters, a cluster analysis (two groups) was performed and differences with regard to risk factors were assessed between clusters. RESULTS: Ocular blood flow data in the two clusters indicated that the two groups (cluster 1 = 26 patient with higher blood flow values; cluster 2 = 30 patients with lower blood flow values) differed mainly in choroidal and optic nerve blood flow. No differences in sex distribution, propensity to have normal tension glaucoma, age, endothelin-1 plasma levels, visual field damage, intraocular pressure, or systemic blood pressure parameters were observed between the two clusters. However, 12 patients (46%) from the cluster with high ocular blood flow values showed a vasospastic response in nailfold capillaroscopy, while such a response was observed in 24 patients (80%) of the cluster with low ocular blood flow values. This difference in vasospastic propensity was statistically significant (p = 0.0121). CONCLUSIONS: Ocular blood flow alterations in glaucoma patients seem, at least partly, to be related to a systemic vascular dysregulation.
This study was designed to assess the effects of rivastigmine (Exelon) on the cognitive functioning of patients suffering from dementia with Lewy bodies. This was a prospective, multi-centre, randomised, double-blind, placebo-controlled exploratory study conducted at sites in the UK, Spain and Italy. The treatment period was 20 weeks with a 3-week posttreatment follow-up. The primary outcome measures were the Cognitive Drug Research (CDR) computerised assessment system and the Neuropsychiatric Inventory. Testing was conducted prior to dosing and then again at weeks 12, 20 and 23. Analysis of the data from the 92 patients who completed the study identified a significant pattern of benefits of rivastigmine over placebo on the CDR system. These benefits were seen on tests of attention, working memory and episodic secondary memory. Taking attention for example, patients given placebo showed a significant deterioration from predosing scores at 12 and 20 weeks, whereas patients on rivastigmine performed significantly above their predosing levels. These effects were also large in magnitude, the decline under placebo at week 12 being 19%, while the improvement under rivastigmine was 23%. The clinical relevance of this 23% improvement was that it took the patients 33% towards being normal for their age on this assessment of attention. These benefits to cognitive function were accompanied by a significant improvement of the other primary outcome measure, the Neuropsychiatric Inventory. Three weeks after discontinuation of rivastigmine, most parameters of cognitive performance returned to predrug levels.
Despite recognition that cholinesterase inhibitors can provide clinical benefits for patients with Alzheimer's disease (AD), the average durations of treatment and beneficial effects are not optimal in all cases. This may be due to disappointing efficacy or poor tolerability of the initial treatment, as well as secondary efficacy failure or adverse effects emerging during the maintenance phase. In such cases, pharmacological differences between available cholinesterase inhibitors provide a good rationale to switch to another drug in the same class. The pharmacological properties of rivastigmine, a dual inhibitor of acetylcholinesterase (AChE) and butyrylcholinesterase, and donepezil and galantamine, two AChE-selective inhibitors, are reviewed. Rivastigmine is reported to show brain- and brain region-selectivity. Donepezil appeared to be more selective for central than peripheral enzymes in rats. Galantamine and donepezil have also been shown to exert nicotinic receptor allosteric modulation in vitro, while rivastigmine has been shown to increase binding of acetylcholine to nicotinic receptors in the AD brain. Donepezil and galantamine are metabolised by the hepatic CYP450 system, whereas rivastigmine is metabolised by its target enzymes. Several switching studies indicated that a substantial proportion of patients who fail to benefit from treatment with donepezil could draw benefits after being switched to rivastigmine. An immediate switch from donepezil to rivastigmine was reported to be well tolerated and was not associated with cholinergic side effects. A post hoc analysis of a 5-month trial with galantamine showed that patients had similar efficacy outcomes, whether or not they had received prior anticholinesterase therapy, suggesting that a previous failure to respond to another cholinesterase inhibitor did not predict response to galantamine. On the basis of available data it is suggested that patients not tolerating or not responding to one particular cholinesterase inhibitor may still draw benefits upon switching to another.
We report the safety results in nine patients with advanced idiopathic Parkinson's disease (PD) who underwent ablative surgery of unilateral subthalamic nucleus (STN). In eight patients, surgical objectives were attained without induction of abnormal involuntary movements or other adverse effects. One patient developed transient hemiballistic movements which improved within 2 weeks after surgery. Assessment at 2 weeks to 20 months postoperatively revealed no long-term adverse effects. We conclude that hemiballism following unilateral ablation of STN in patients with PD is a rare phenomenon, and unilateral ablative lesions of STN can be performed safely.
We report on a 28-year-old woman with insulin-resistant diabetes mellitus with a 5-year history of progressive stiffness and painful spasms of the right leg, exaggerated by sudden auditory and tactile stimuli or by emotional stress. There were no signs of truncal rigidity or exaggerated lumbar lordosis. Anti-glutamic acid decarboxylase antibodies were positive in her serum. She improved substantially with clonazepam 4 mg/day. She presented with electrophysiological findings not previously reported in stiff leg syndrome, which may suggest increased inhibition in the uninvolved upper extremities.
We report an unusual case of celiac disease in a 31-year-old woman with gait disorder, stimulus-induced myoclonus and abnormalities of eye movement. We suggest that celiac disease can present with a variety of unusual neurological manifestations.
Treatment of dementia can be divided as symptomatic treatment of cognitive or non-cognitive symptoms and the treatment of underlying pathology. In the last decade the thrust of symptomatic treatment of Alzheimer's disease (AD) has been enhancement of cholinergic transmission. Besides the acetycholinesterase inhibitors (AChE-I) currently in use, cholinergic agonists and enhancers are in development. Other therapeutic approaches directed towards neurotransmitter substitution or modulation include serotoninergic, noradrenergic substances, neuropeptides and those acting via excitatory amino acid receptors, such as ampakines or NMDA antagonists. Introduction of atypical neuroleptics represents the most recent development in the treatment of behavioural symptoms. Efforts to treat the underlying pathology are based on modulation of APP processing in order to decrease the accumulation of beta-amyloid, those to decrease tau hyperphosphorylation, use of nerve growth factors and those based on Apo-E modulation. Potential use of oestrogens and NSAIDs are also under investigation. Recently, vaccination with amyloid-beta peptide has been reported to be effective in an animal model of AD, this putative vaccine is now in clinical trials. Likewise, recent studies suggest that some statins may have a prophylactic effect.
BACKGROUND: Dementia with Lewy bodies is a common form of dementia in the elderly, characterised clinically by fluctuating cognitive impairment, attention deficits, visual hallucinations, parkinsonism, and other neuropsychiatric features. Neuroleptic medication can provoke severe sensitivity reactions in patients with dementia of this type. Many deficits in cholinergic neurotransmission are seen in the brain of patients with Lewy-body dementia; therefore, drugs enhancing central cholinergic function represent a rationally-based therapeutic approach to this disorder. Rivastigmine, a cholinesterase inhibitor, was tested in a group of clinically characterised patients with Lewy-body dementia. METHODS: A placebo-controlled, double-blind, multicentre study was done in 120 patients with Lewy-body dementia from the UK, Spain, and Italy. Individuals were given up to 12 mg rivastigmine daily or placebo for 20 weeks, followed by 3 weeks rest. Assessment by means of the neuropsychiatric inventory was made at baseline, and again at weeks 12, 20, and 23. A computerised cognitive assessment system and neuropsychological tests were also used, and patients underwent close medical and laboratory safety analysis. FINDINGS: Patients taking rivastigmine were significantly less apathetic and anxious, and had fewer delusions and hallucinations while on treatment than controls. Almost twice as many patients on rivastigmine (37, 63%), than on placebo (18, 30%), showed at least a 30% improvement from baseline. In the computerised cognitive assessment system and the neuropsychological tests, patients were significantly faster and better than those on placebo, particularly on tasks with a substantial attentional component. Both predefined primary efficacy measures differed significantly between rivastigmine and placebo. After drug discontinuation differences between rivastigmine and placebo tended to disappear. Known adverse events of cholinesterase inhibitors (nausea, vomiting, anorexia) were seen more frequently with rivastigmine than with placebo, but safety and tolerability of the drug in these mostly multimorbid patients were judged acceptable. INTERPRETATION: Rivastigmine 6-12 mg daily produces statistically and clinically significant behavioural effects in patients with Lewy-body dementia, and seems safe and well tolerated if titrated individually.