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1.
There is significant interest in the development of new drugs to treat vascular dementia. However, before US approval of new drugs for this entity is possible, certain issues with regulatory implications need to be addressed. Is vascular dementia a distinct clinical syndrome with valid diagnostic criteria? Can this entity be distinguished from Alzheimer's disease (AD) and other causes of dementia? What design features are important for clinical trials in this disorder? The US Food and Drug Administration (FDA) convened a special meeting of the Peripheral and Central Nervous System Advisory Committee in an attempt to answer these questions. The conclusions from this meeting indicate that vascular dementia (VaD) is a pathologically heterogeneous disorder but appears to be reasonably distinguishable from AD dementia. The NINDS-AIREN diagnostic criteria are suitable as entry criteria for vascular dementia trials. Trials should be similar in duration to AD dementia trials and should employ a dual outcome strategy (cognitive + global/functional measures). For drugs that are believed to have a disease-modifying effect, clinical trials should study specific vascular dementia subtypes and would need to employ substantially different designs from those used currently. The term "vascular dementia" may not be entirely appropriate to describe this population. 相似文献
2.
The SKT neuropsychological test battery. 总被引:1,自引:0,他引:1
The SKT is a brief neuropsychological test battery that includes nine performance subtests that define two independent factors of memory and attention deficit. It requires no more than 15 minutes to administer and has five parallel forms. Developed in Germany, it has been used successfully to document improved performance of patients in trials of antidementia drugs in that country. This article addresses factor structure and scoring, dementia profile classification, reliability, and validity data. The SKT appears to hold promise for efficient assessment of objective performance changes to supplement clinical evaluations of therapeutic efficacy of new drugs for treatment of senile dementia. 相似文献
3.
M G Bousser 《L'Encéphale》1977,3(4):357-372
The incidence of both atherosclerosis and demential increases with age and therefore the terms "cerebral atherosclerosis" or "cerebro-vascular dementia" are commonly used for any mental deterioration in elderly persons. These names depend on the proposition of a gradual narrowing of cerebral arteries as an inevitable accompaniement of ageing which ends in dementia through a progressive reduction of cerebral blood flow. This apparently reasonnable hypothesis has now been shown to be wrong. ;t has been established that first, senile dementia is not due to cerebral atherosclerosis in spite of the frequent coexistence of degenerative and vascular lesions; and secondly, true cerebro vascular dementia results from the destruction of brain tissue following cerebral infarction; hence the proper term is "multi-infarct dementia". This neuronal destruction leads to decrease in cerebral metabolism and blood flow and to intellectual deterioration. The diagnostic criteria are therefore those of cerebral infarcts i.e: arterial hypertension and/or signs of atherosclerosis, sudden onset and/or stepwise progression, and focal neurological signs. If one follow those criteria, multi-infarct dementia accounts for only about 10% of all dementias; if one does not, the diagnosis will continue to be made to the exclusion of other potentially curable causes of dementias. Five clinico-pathological forms can be distinguished according to the size, number and site of the infarcts: lacunar state, large multiple infarcts, watershed infarction, single infarct and Binswanger's encephalopathy. This distinction is always arbitrary because the association of lacunes and large infarcts is very common in multi-infarct dementia. The almost invariable failure of all therapeutic measures once multi-infarct dementia has been established stresses the importance of prevention. This depends on prevention of cerebral infarcts, i.e. on the correction of risk factors amongst which arterial hypertension is by far, the most important. Some cases benefit also from carotid surgery, anticoagulants, and antiplatelet drugs but antihypertensive drugs are the most essential part. It is very likely that if all cases of arterial hypertension are properly treated, the incidence of multi-infarct dementia will decrease greatly. 相似文献
4.
Recent epidemiological reports suggest that statins, and possibly other lipid lowering agents, might be protective for Alzheimer disease, and for other types of dementia. Importantly, however, epidemiological reports of this type are susceptible to indication bias, i.e. people who elect to take lipid-lowering agents might be healthier than those who do not, so that it may be these other health factors which explain their lower risk of dementia. Limited clinical trials data support the notion that statins, in particular, have important effects on cerebral cholesterol metabolism, but the link to clinical effects in dementia has yet to be established, and the mechanisms by which lipid lowering agents might confer protective effects is unclear. Dedicated clinical trials are now under way, and their results are awaited with great interest. 相似文献
5.
Alzheimer's disease, one of the most common forms of dementia, is a neurodegenerative disorder characterized by progressive cognitive decline and affects as many as 5.3 million people in United States alone. Both Alzheimer's and dementia have tripled the cost of health care for elderly people, amounting to about $148 billion each year. Although there have been numerous drugs designed so far, no ideal or successful drug treatment for Alzheimer's and dementia has been translated into clinical setups. One of the most widely accepted theories of Alzheimer's pathology is the aggregation of amyloid-beta (Aβ) into extracellular cortical and hippocampal plaques. It has also been postulated that excessive cholesterol build-up in the brain plays an integral role in Aβ aggregation, and using HMG-coA reductase inhibitors may reduce Aβ accumulation by lowering brain cholesterol levels. Based on the success of animal studies and phase II clinical trials, HMG-coA reductase inhibitors may provide a viable alternative therapy in AD treatment. This review highlights the results of both pre-clinical and clinical trials on HMG-coA reductase inhibitors in order to give a comprehensive overview of their recent progress in Alzheimer's disease research. 相似文献
6.
Effect of long-term treatment with tacrine (THA) in Alzheimer's disease as visualized by PET 总被引:3,自引:0,他引:3
A. Nordberg 《Acta neurologica Scandinavica》1993,88(S149):62-65
Among various attempts to enhance cholinergic neurotransmission in AD clinical trials with cholinesterase inhibitors have been most promising. In this study positron emission tomography (PET) was used to investigate how long-term treatment with cholinesterase inhibitors like tacrine could induce changes in the functional activity of Alzheimer brains. PET investigations measuring cerebral blood flow, glucose metabolism, nicotinic and muscarinic receptors have repeatedly been performed in patients treated with tacrine up to 2.5 years. Changes in nicotinic receptors and blood flow were observed after 3 weeks of treatment while changes in glucose metabolism were measured after 3 months of treatment. Following longer period of treatments and increase in dose of tacrine improvements were measured by PET. The most significant effects were found in patients with early forms of the dementia. The findings suggest that longer treatment may not only be symptomatic but might slow down the disease process. 相似文献
7.
Honig LS 《Archives of neurology》2012,69(8):969-977
Dementia disorders are characterized by clinicopathological criteria. Molecular understandings of these disorders, based on immunohistochemical studies, biochemical investigations, genetic approaches, and animal models, have resulted in advances in diagnosis. Likewise, translational research has allowed us to apply our increasing basic scientific knowledge of neurodegeneration to the rational development of new investigational therapies based on our current understanding of disease pathogenesis. This review discusses the application of translational research to both diagnosis and treatment of dementia disorders. The development of biomarkers has yielded imaging and biochemical methods that assist the physician more than ever in the diagnosis of neurodegenerative dementias, especially Alzheimer disease. New diagnostic criteria for disease are based on these molecular-based techniques. And these biomarkers are of potential use in monitoring disease activity during therapeutic trials. Translational investigations likewise have led toward new avenues in targeted dementia research. This is particularly so in the development and testing of disease-modifying treatments that might slow or deter progressive deterioration. Recent clinical trials have not been based on empirical trials of established drugs but, rather, on trials of drugs shown, through experiments in biochemical, cell culture, and animal models, to interfere with known elements of the pathogenetic cascade of Alzheimer disease. 相似文献
8.
In developed countries, ischemic stroke is one of the leading causes of death and neurological impairment. The two most important therapeutic approaches in patients with acute cerebral ischemia consist of improving cerebral blood flow and blocking the biochemical and metabolic changes at the ischemic cascade level. The significant advances made in the past decade in the knowledge of the physiopathological mechanisms of cerebral ischemia, and the development of new drugs have given rise to true expectations regarding treatment and the rejection of nihilist attitudes. In the past 15 years, based on the excellent results obtained in experimental models of ischemia, many clinical trials have been conducted with different neuroprotective drugs. The results obtained in most studies have been negative, or the studies were terminated early owing to side effects. However, some drugs (citicoline, clomethiazole, piracetam and ebselen) have shown a certain degree of clinical efficacy, limited to subgroups of patients, and with a narrow therapeutic window, longer-lasting in the case of citicoline. The design of new clinical trials with neuroprotective drugs requires adequate preclinical assessment and the use of the new magnetic resonance techniques for the selection of patients and the assessment of the efficacy of treatment. The new trends in neuroprotection in focal cerebral ischemia and the results of the clinical trials published to date are reviewed. 相似文献
9.
Kirk A 《The Canadian journal of neurological sciences. Le journal canadien des sciences neurologiques》2007,34(Z1):S42-S46
The Cognitive section of the Alzheimer's Disease Assessment Scale (ADAS-Cog) remains the most widely used cognitive measure in dementia trials although it does not assess attention, executive function, or agnosia. Designed for use in Alzheimer's disease (AD), it may not be ideal in assessing patients with other diagnoses. The ADAS-Cog differentiates between AD patients, patients with Mild Cognitive Impairment, and normal controls. It has been used in trials of drugs for vascular and mixed dementia and dementia with Lewy bodies. It is not clear that the ADAS-Cog is adequate for assessing cognition in frontotemporal dementia. Well-validated aphasia batteries, such as the Western Aphasia Battery, can be used to assess language. Brief tests of frontal function such as the Frontal Assessment Battery or the Executive Interview might be useful additions in frontotemporal dementia trials. The most widely used assessment tool for patients with advanced dementia is the Severe Impairment Battery. The domains tested are analogous to those assessed by the ADAS-Cog. The Mini-Mental State Exam and the Modified Mini-Mental State Examination are useful in stratifying patients for trial entry. Cognitive measures better tailored to the diseases in question are needed for non-Alzheimer dementias. 相似文献
10.
Pantoni L 《Journal of the neurological sciences》2004,226(1-2):67-70
A considerable number of therapeutic trials have been performed in vascular dementia (VaD). The results of these trials have generally been considered as disappointing and no drug treatment has been so far approved for the treatment of VaD by regulatory agencies. The aim of the present paper is to critically review the results of randomized clinical trials performed with non-cholinergic drugs in VaD. The conclusions of the present review are that: (1) some drugs such as nicergoline, memantine, posatirelin, propentofylline, and pentoxifylline have shown some, although partly limited, benefits in VaD patients; (2) besides a lack of efficacy of the tested drugs, possible causes of the negative results of many randomized clinical trials in VaD are the enrollment of patients with heterogeneous subtypes of VaD, the small sample size, and the use of end-points and cognitive tests inadequate for the VaD setting because derived from previous experience in the field of Alzheimer disease. Preliminary analyses show that focusing therapeutic trials on specific forms of VaD such as the subcortical type may lead to results different from those obtained in a heterogeneous VaD group. This selective focus seems to be better suited for disclosing specific treatments in the field of VaD. 相似文献
11.
Feldman HH Jacova C 《The Canadian journal of neurological sciences. Le journal canadien des sciences neurologiques》2007,34(Z1):S84-S89
Prevention in Alzheimer's disease and other dementias (AD/dementia) is defined on the basis of clinical states and their expressed symptoms. Primary prevention refers to delaying the development of the full-blown state of clinically expressed disease in normal individuals. Current primary prevention research is driven by evidence of AD/dementia protective factors that have emerged from epidemiological studies. The first randomized controlled trials (RCTs) of primary AD/dementia prevention have been designed to test the efficacy and safety of NSAIDs, hormonal therapy, antihypertensive drugs and antioxidants. The experience of these trials has indicated safety concerns as a key issue and highlighted significant design challenges in this type of research. These trials have required large sample sizes and unsustainable costs. There should be consideration given in future trials to enriching study samples with risk factors to increase progression rates to AD/dementia. Innovative strategies will also be needed to recruit and retain subjects given the long follow-up periods, modest perceived benefit and the potential for the risk-benefit ratio to change during the trial. It is foreseeable that regulatory authorities will be presented with primary prevention RCTs for approval and labelling, and that criteria to evaluate such evidence still need to be developed. 相似文献
12.
Lipton SA 《Current Alzheimer research》2005,2(2):155-165
In western countries, Alzheimer's disease (AD) is the most common form of dementia. In fact, if left uncurbed, the economic cost of caring for AD patients could consume the entire gross national product of the USA by the middle of this century. Until recently, the only available drugs for this condition were cholinergic treatments, which symptomatically enhance cognitive state to some degree, but they were not neuroprotective. In fact, many potential neuroprotective drugs tested in clinical trials failed because they were poorly tolerated. However, after our discovery of its clinically-tolerated mechanism of action, one neuroprotective drug, memantine, was recently approved by the European Union and the U.S. Food and Drug Administration (FDA) for the treatment of Alzheimer's disease. Recent phase 3 clinical trials have shown that memantine is effective in the treatment of both mild and moderate-to-severe Alzheimer's disease and possibly vascular dementia (multi-infarct dementia). Here we review the molecular mechanism of memantine's action and also the basis for the drug's use in these neurological diseases, which are mediated at least in part by excitotoxicity. Excitotoxicity is defined as excessive exposure to the neurotransmitter glutamate or overstimulation of its membrane receptors, leading to neuronal injury or death. Excitotoxic neuronal cell death is mediated in part by overactivation of N-methyl-d-aspartate (NMDA)-type glutamate receptors, which results in excessive Ca2+ influx through the receptor's associated ion channel. Physiological NMDA receptor activity, however, is also essential for normal neuronal function. This means that potential neuroprotective agents that block virtually all NMDA receptor activity will very likely have unacceptable clinical side effects. For this reason many previous NMDA receptor antagonists have disappointingly failed advanced clinical trials for a number of neurodegenerative disorders. In contrast, studies in our laboratory have shown that the adamantane derivative, memantine, preferentially blocks excessive NMDA receptor activity without disrupting normal activity. Memantine does this through its action as an uncompetitive, low-affinity, open-channel blocker; it enters the receptor-associated ion channel preferentially when it is excessively open, and, most importantly, its off-rate is relatively fast so that it does not substantially accumulate in the channel to interfere with normal synaptic transmission. Clinical use has corroborated the prediction that memantine is thus well tolerated. Besides Alzheimer's disease, memantine is currently in trials for additional neurological disorders, including other forms of dementia, depression, glaucoma, and severe neuropathic pain. A series of second-generation memantine derivatives are currently in development and may prove to have even greater neuroprotective properties than memantine. These second-generation drugs take advantage of the fact that the NMDA receptor has other modulatory sites in addition to its ion channel that potentially could also be used for safe but effective clinical intervention. 相似文献
13.
Structural magnetic resonance imaging in the practical assessment of dementia: beyond exclusion 总被引:6,自引:0,他引:6
Neuroimaging is increasingly used to aid diagnosis in dementia. The traditional view that imaging is important solely as means of excluding treatable causes of dementia is maintained by many guidelines. These conditions however, account for a tiny proportion (<1%) of all causes of dementia. Over the past few years it has been recognised that a more accurate diagnosis and prognosis is important for patients and their families. The different pathological processes that produce cerebral dysfunction at a cellular level also produce macroscopic effects that can be detected in vivo with imaging. Clinically useful measures that distinguish between neurodegenerative disorders at an early stage are still awaited. The most likely future use of structural imaging will be the identification of patients at risk for Alzheimer's disease or with preclinical Alzheimer's disease. For magnetic resonance imaging (MRI) this will mean focusing on those areas that are affected earliest in the disease; ie, entorhinal cortex and hippocampus, using high resolution structural MRI or sophisticated brain mapping techniques. Imaging research is also likely to focus on measuring progression and detecting therapeutic effect. As such, MRI is already become an indispensable tool in clinical trials in dementia. 相似文献
14.
The most successful approach for treating people with Alzheimer's disease to date has been by improving cholinergic transmission using cholinesterase inhibitors. Many of these drugs selectively inhibit acetylcholinesterase but some agents inhibit both acetylcholinesterase and butyrylcholinesterase. Recent evidence from studies examining butyrylcholinesterase in post mortem brain samples from dementia patients and examining the relationship between butyrylcholinesterase polymorphisms and the progression of cognitive impairment in dementia with Lewy bodies and Alzheimer's disease add to a body of work suggesting that butyrylcholinesterase is present in key brain areas and may influence the maturation of plaques in Alzheimer's disease. These accumulating data suggest that butyrylcholinesterase contributes to disease progression in people with dementia, which may be particularly important in individuals with more severe dementia as butyrylcholinesterase activity increases with disease development. It is a priority for future clinical trials to determine whether agents which inhibit butyrylcholinesterase and acetylcholinesterase have a greater clinical efficacy. 相似文献
15.
Weiser M Rotmensch HH Korczyn AD Hartman R Cicin-Sain A Anand R;Rivastigmine-Risperidone Study Group 《International journal of geriatric psychiatry》2002,17(4):343-346
BACKGROUND: The majority of patients with Alzheimer's disease (AD) or vascular dementia display, in addition to cognitive impairment, various degrees of behavioral disturbances. As the use of cholinesterase inhibitors for the treatment of cognitive impairment in dementia becomes widespread, many of these patients will be treated concomitantly with cholinesterase inhibitors and with anti-psychotic drugs to ameliorate behavioral disturbances. Despite the widespread use of this combination in clinical practice, the safety and tolerability of such combination therapy has not been evaluated in controlled clinical trials. This pilot study examined the effects of addition of risperidone 0.5-2 mg/day to patients on rivastigmine 3-12 mg/day, and vice versa. METHODS: 65 patients suffering from AD, 10 from vascular dementia, and 15 from both were randomized to open label rivastigmine and risperidone, alone or in combination, for 20 weeks. Adverse events caused by co-administration were assessed. RESULTS: No clinically relevant adverse interactions were observed. CONCLUSIONS: These preliminary results indicate that rivastigmine and risperidone can be safely co-administered. Confirmation of these results in large clinical trials studies is warranted. 相似文献
16.
Fisher M 《Cerebrovascular diseases (Basel, Switzerland)》2006,21(Z2):64-70
The development of acute stroke therapies has yielded only limited success and many failures in multiple clinical trials. The target of acute stroke therapy is that portion of the ischemic region that is still potentially salvageable, i.e. the ischemic penumbra. Neuroprotective drugs have the potential to prevent a portion of the ischemic penumbra from evolving into infracted tissue and designing trials that target neuroprotective drugs at patients with persistent penumbra should enhance the likelihood of a positive outcome. Currently, diffusion and perfusion MRI has the potential to approximate the location and persistence of the ischemic penumbra and can be used in clinical trials to select appropriate patients for inclusion and to evaluate a meaningful treatment effect. Perfusion CT may also have similar capabilities. Use of these imaging modalities in clinical trials and ultimately in clinical practice will likely help in the development and utilization of novel neuroprotective drugs. 相似文献
17.
Jönsson L Jönsson B Wimo A Whitehouse P Winblad B 《Alzheimer disease and associated disorders》2000,14(3):137-140
The Second International Pharmacoeconomic Conference on Alzheimer's Disease was held in Stockholm, Sweden, on April 4, 2000. The presentations focused on the role of cognition in pharmacoeconomic evaluations, the costs and consequences of behavioral disturbances, quality of life, disease progression models, and methods for valuing informal care. The results from individual studies will be published separately. Cognition has been used as the sole measure of disease severity in economic evaluations in dementia. However, behavioral disturbances are an important determinant of both cost and quality of life and should also be considered when appraising the effect of treatment. Quality-of-life assessment constitutes a single measure of the total impact of the disease, as well as a way of quantifying the benefits of treatment with antidementia drugs so that they can be compared with interventions in other disease areas. Measuring the quality of life of patients with dementia is associated with methodologic difficulties related to the difficulties for some patients in completing usual assessment processes. Disease progression models may be helpful in extrapolating the results from clinical trials to longer time periods and more representative populations. Modeling is an unavoidable part of the economic evaluation of antidementia drugs, and efforts should be made to increase transparency and comparability among models. Informal care constitutes a large percentage of the total care for patients with dementia, and the valuation of these services has a large impact on the results of pharmacoeconomic evaluations. Difficulties lie in quantifying the time spent on caring for the elderly and in attaching the correct price to each unit of time. The contingent valuation method is an alternative way of valuing informal care that so far has not been used in the field of dementia. 相似文献
18.
Lon S Schneider Karen Dagerman Philip S Insel 《The American journal of geriatric psychiatry》2006,14(3):191-210
OBJECTIVE: Atypical antipsychotic medications are widely used to treat delusions, aggression, and agitation in people with Alzheimer disease (AD) and other dementia. Several clinical trials have not shown efficacy, and there have been concerns about adverse events. The objective of this study was to assess the evidence for efficacy and adverse events of atypicals for people with dementia. METHODS: MEDLINE, the Cochrane Register of Controlled Trials, meetings, presentations, and information obtained from sponsors were used in this study. Published and unpublished randomized, placebo-controlled, double-blind, parallel-group trials in patients with AD or dementia of atypical antipsychotics marketed in the United States were studied. Clinical and trials characteristics, outcomes, and adverse events were extracted. Data were checked by a second reviewer. Fifteen trials including 16 contrasts of atypical antipsychotics with placebo met selection criteria: aripiprazole (k = 3), olanzapine (k = 5), quetiapine (k = 3), and risperidone (k = 5). A total of 3,353 patients were randomized to drug and 1,757 to placebo. Standard meta-analysis methods were used to summarize outcomes. RESULTS: Quality of the reporting of trials varied. Efficacy on rating scales was observed by meta-analysis for aripiprazole and risperidone, but not for olanzapine. Response rates were frequently not reported. There were smaller effects for less severe dementia, outpatients, and patients selected for psychosis. Approximately one-third dropped out without overall differences between drug and placebo. Adverse events were mainly somnolence and urinary tract infection or incontinence across drugs, and extrapyramidal symptoms or abnormal gait with risperidone or olanzapine. Cognitive test scores worsened with drugs. There was no evidence for increased injury, falls, or syncope. There was a significant risk for cerebrovascular events, especially with risperidone; increased risk for death overall was reported elsewhere. CONCLUSIONS: Small statistical effect sizes on symptom rating scales support the evidence for the efficacy of aripiprazole and risperidone. Incomplete reporting restricts estimates of response rates and clinical significance. Dropouts and adverse events further limit effectiveness. Atypicals should be considered within the context of medical need and the efficacy and safety of alternatives. Individual patient meta-analyses are needed to better assess clinical significance and effectiveness. 相似文献
19.
Dementia with Lewy bodies (DLB) is the second most frequent cause of primary degenerative dementias, following Alzheimer's disease (AD). The nosologic situation of this disease has fragile limits. There is controversy as to whether Parkinson's disease (PD) and DLB are two different entities or whether they make up part of the same spectrum. The terms diffuse Lewy bodies disease and the variant of Lewy bodies in senile dementia or AD have been used to describe pathologic changes with clinical manifestations of dementia and parkinsonism. At present, DLB should be understood as an entity with the essential feature being the presence of Lewy bodies in the brain stem and cerebral cortex. From the point of view of clinical examination, DLB is characterized by the presence of subcortical or progressive cortical dementia, at times without severe memory disorders, with great fluctuations and well detailed recurrent visual hallucinations. These cognitive alterations are associated with parkinsonism. Other frequent disorders are falls, syncopes, transitory alterations in consciousness, great sensitivity to neuroleptic drugs and visual illusions with pseudoperception. The correct diagnosis of this entity is important to administer adequate treatment, to avoid classical neuroleptic drugs and to establish precise prognosis. From a therapeutic point of view, cholinesterase inhibitors show some efficacy in the treatment of cognitive alterations. 相似文献
20.
Jelic V Kivipelto M Winblad B 《Journal of neurology, neurosurgery, and psychiatry》2006,77(4):429-438
Mild cognitive impairment (MCI) is an operational definition for a cognitive decline in individuals with a greater risk of developing dementia. The amnestic subtype of MCI is of particular interest because these individuals most likely progress to Alzheimer's disease (AD). Currently hypothesised therapeutic approaches in MCI are mainly based on AD treatment strategies. Long term secondary prevention randomised clinical trials have been completed in amnestic MCI populations, encompassing agents with various mechanisms of action: acetylcholinesterase inhibitors (donepezil, rivastigmine, galantamine), antioxidants (vitamin E), anti-inflammatories (rofecoxib), and nootropics (piracetam). The design of clinical trials in MCI is influenced by study objectives and definition of primary end points: time to clinical diagnosis of dementia, and AD in particular, or symptom progression. As none of the drugs previously shown to have clinical efficacy in AD trials or benefit in everyday practice have met the primary objectives of the respective trials, design of future clinical trials in MCI should be further developed particularly as regards the selection of more homogeneous samples at entry, optimal treatment duration, and multidimensional and reliable outcomes. 相似文献