scispace - formally typeset
Search or ask a question
Journal ArticleDOI

Clinical practice with anti-dementia drugs: A revised (third) consensus statement from the British Association for Psychopharmacology

TL;DR: The British Association for Psychopharmacology coordinated a meeting of experts to review and revise its previous 2011 guidelines for clinical practice with anti-dementia drugs, with the consensus statement focusing on medication.
Abstract: The British Association for Psychopharmacology coordinated a meeting of experts to review and revise its previous 2011 guidelines for clinical practice with anti-dementia drugs. As before, levels of evidence were rated using accepted standards which were then translated into grades of recommendation A-D, with A having the strongest evidence base (from randomised controlled trials) and D the weakest (case studies or expert opinion). Current clinical diagnostic criteria for dementia have sufficient accuracy to be applied in clinical practice (B) and both structural (computed tomography and magnetic resonance imaging) and functional (positron emission tomography and single photon emission computerised tomography) brain imaging can improve diagnostic accuracy in particular situations (B). Cholinesterase inhibitors (donepezil, rivastigmine, and galantamine) are effective for cognition in mild to moderate Alzheimer's disease (A), memantine for moderate to severe Alzheimer's disease (A) and combination therapy (cholinesterase inhibitors and memantine) may be beneficial (B). Drugs should not be stopped just because dementia severity increases (A). Until further evidence is available other drugs, including statins, anti-inflammatory drugs, vitamin E, nutritional supplements and Ginkgo biloba, cannot be recommended either for the treatment or prevention of Alzheimer's disease (A). Neither cholinesterase inhibitors nor memantine are effective in those with mild cognitive impairment (A). Cholinesterase inhibitors are not effective in frontotemporal dementia and may cause agitation (A), though selective serotonin reuptake inhibitors may help behavioural (but not cognitive) features (B). Cholinesterase inhibitors should be used for the treatment of people with Lewy body dementias (both Parkinson's disease dementia and dementia with Lewy bodies), and memantine may be helpful (A). No drugs are clearly effective in vascular dementia, though cholinesterase inhibitors are beneficial in mixed dementia (B). Early evidence suggests multifactorial interventions may have potential to prevent or delay the onset of dementia (B). Though the consensus statement focuses on medication, psychological interventions can be effective in addition to pharmacotherapy, both for cognitive and non-cognitive symptoms. Many novel pharmacological approaches involving strategies to reduce amyloid and/or tau deposition in those with or at high risk of Alzheimer's disease are in progress. Though results of pivotal studies in early (prodromal/mild) Alzheimer's disease are awaited, results to date in more established (mild to moderate) Alzheimer's disease have been equivocal and no disease modifying agents are either licensed or can be currently recommended for clinical use.

Summary (8 min read)

Introduction

  • The British Association for Psychopharmacology (BAP) produced a first edition of clinical practice guidelines for antidementia drugs in 2006 (Burns and O'Brien, 2006) , which were subsequently revised (O'Brien and Burns, 2011) .
  • The focus was on new evidence which had become available since the first guidelines were published.
  • There is general agreement that anticholinergic burden should be minimised in those with dementia, especially before prescribing cholinergic medication.
  • Concerns over cerebrovascular adverse events and increased mortality has forced consideration of alternative approaches to the treatment of BPSD, including ChEIs, memantine and increased the emphasis on non-pharmacological therapies including activity, music therapy and aromatherapy.

Methodology

  • The participants were selected for their clinical and research experience in the field of dementia care, and also included a person with dementia.
  • The group arrived at its decisions after expert papers were written independently and then presented and discussed at the meeting.
  • All relevant papers published up to and including December 2015 were considered.
  • Particular emphasis was placed on reviewing the previous recommendations in the light of new evidence published since the last guidelines.
  • Assess the evidence for the efficacy of currently available anti-dementia drugs in all common types of dementia and, based on that, make clear recommendations for clinical practice.

Diagnosis and investigations

  • The criteria used to define dementia and cognitive disorders continue to cause controversy.
  • Two key changes from the fourth edition (DSM-IV; American Psychiatric Association, 2000) of relevance here are (a) a move away from the terms of dementia and mild cognitive impairment to major and mild neurocognitive disorder respectively and (b) the inclusion of Lewy body disorder (major or mild neurocognitive disorder with Lewy bodies).
  • The National Institute on Aging-Alzheimer's Association (NIA-AA) group has published new criteria for AD dementia (McKhann et al., 2011) , mild cognitive impairment due to AD (Albert et al., 2011) and preclinical AD (Sperling et al., 2011) .
  • The main purpose of many of these changes has been to allow internationally agreed criteria to be used for subject selection and stratification for ongoing natural history and therapeutic studies, though the validation and clinical usefulness of these criteria remains to be fully determined.
  • Clinical criteria for frontotemporal dementia (FTD) have been updated (Rascovsky et al., 2011) .

Neuroimaging and cerebrospinal fluid (CSF) biomarkers

  • There is increasing interest in the use of brain imaging and CSF biomarkers, both to assist with early and accurate differential diagnosis, and as potential markers of disease progression which may be used as surrogate outcome measures for clinical trials.
  • AD is associated with medial temporal lobe atrophy, particularly of the entorhinal cortex and hippocampus, and temporoparietal hypoperfusion on SPECT and hypometabolism on FDG PET.
  • Decreased cardiac sympathetic uptake, as indicated by decreased metaiodobenzylguanidine (MIBG) SPECT binding has been found in Parkinson's disease and DLB.
  • Raised levels of CSF tau (both total and phosphorylated tau) and reduced levels of Aβ1-42 have proved, when combined in a ratio, to have reasonable diagnostic accuracy for separating AD from other dementias (mean sensitivity 72%, mean specificity 78% when comparing AD to other dementias) (Mitchell, 2009) .
  • Table 2 provides a summary of assessment and diagnosis recommendation strengths.

Drug treatments for Alzheimer's disease

  • Since the previous revision of the guidelines no new drugs have been licensed for AD.
  • Donepezil, rivastigmine and galantamine are licensed for mild to moderate AD, memantine for moderate to severe AD, and several randomised controlled trials (RCTs) demonstrate their efficacy in these situations.
  • The basic evidence to support the use of these drugs remains unchanged and, in general, the costs of the drugs are now significantly lower, particularly for donepezil.
  • Combination therapy using a ChEI initially with the later addition of memantine is now considered optimal treatment in many countries particularly as the dementia advances.
  • No new comparative trials between the three ChEIs, or of trials switching between the ChEIs, have been published in the last.

A

  • There is type II evidence that medial temporal atrophy can be helpful in the diagnosis of Alzheimer's disease, and for distinguishing Alzheimer's disease from dementia with Lewy bodies in some cases.
  • There is type I evidence that amyloid PET imaging can identify patients with elevated amyloid burden in the brain, and so be a useful diagnostic marker for Alzheimer's disease.
  • There is type I evidence that MIBG can differentiate dementia with Lewy bodies from Alzheimer's disease.
  • There is type I evidence that cholinesterase inhibitors should not be stopped just because the point of severe dementia has been reached.
  • HRT should not be prescribed either as a prevention or treatment for dementia, including Alzheimer's disease.

B

  • There is type I evidence that dopaminergic SPECT or PET imaging can help differentiate dementia with Lewy bodies from Alzheimer's disease.
  • It is widely recognised that a good number of people diagnosed with dementia have mixed brain pathology which is predominantly due to Alzheimer's and cerebrovascular changes.
  • Were no different between the intervention and control group.
  • Finally, trials themselves need to be conducted in a limited number of centres with access to the target populations to run at scale and maintain data quality and reduce sample heterogeneity.
  • The EPAD programme concurrently addresses all these elements.

CSF biomarkers

  • There is type II evidence that CSF markers of amyloid and tau may be useful diagnostic markers for Alzheimer's disease, but further standardisation and validation is required before they can be more widely used clinically.
  • Previous comparative trials failed to consistently demonstrate any significant differences in efficacy between the three ChEIs, the main differences found being in frequency and type of adverse events (O'Brien and Burns, 2011) .
  • Similarly, their previous recommendation that a significant proportion (up to 50%) appear to both tolerate and benefit from switching between ChEIs if they cannot tolerate one, remains valid.

Treatment with cholinesterase inhibitors and memantine

  • There is type I evidence showing small cognitive improvements with both cholinesterase inhibitors and memantine in vascular dementia.
  • Benefits in terms of global outcome are not seen and adverse events for cholinesterase inhibitors (but not memantine) are significantly greater than placebo.
  • Evidence indicates that neither cholinesterase inhibitors nor memantine should be prescribed to people with vascular dementia, though those with mixed vascular dementia and Alzheimer's disease may benefit.

Combination therapy

  • B VaD are heterogeneous, ranging from large multiple infarcts caused by emboli to diffuse white matter changes associated with chronic hypoperfusion (O'Brien and Thomas, 2015; O'Brien et al., 2003) .
  • Specific pharmacological interventions have involved donepezil, galantamine, rivastigmine and memantine.
  • The authors commented that the clinical heterogeneity of VaD patients limited generalisability of the trials' outcomes because the effect of treatment on specific patients or subgroups could not be defined.
  • In the SIVD group rivastigmine did not improve MMSE but had beneficial effects upon measures of executive function, neuropsychiatric features, depression and Clinical Dementia Rating.

Cholinesterase inhibitors

  • There is type I evidence to support treatment with rivastigmine and donepezil in Lewy body dementias, both in dementia with Lewy bodies and Parkinson's disease dementia.
  • There is type I evidence that cholinesterase inhibitors are not recommended for the treatment of frontotemporal dementia.

Other dementias

  • This group of disorders is used here to include FTD, the primary progressive aphasias, progressive supranuclear palsy (PSP), corticobasal degeneration (CBD) and prion dementias amongst others, and the overlap between some of these conditions is illustrated in Figure 4 .
  • The existing evidence does not support the use of these drugs in FTD although rates of off-label use remain high, despite increased agitation having been reported with their use in FTD (O'Brien et al., 2011) .
  • A small trial of Souvenaid reported beneficial effects in behaviour and social cognition measures over a short time period (Pardini et al., 2015) , but more studies are needed.
  • Since the last BAP statement there has been no new trial evidence for ChEIs or coenzyme Q10 in treating PSP.
  • There are no adequately powered studies of ChEIs to support the use of these drugs for cognitive impairment in Huntington's disease.

Mild cognitive impairment (MCI) due to AD and prodromal AD

  • There have been no new positive studies to inform prescribing in prodromal conditions such as MCI.
  • Cochrane and other reviews show lack of efficacy of ChEIs (Birks and Flicker, 2006; Loy and Schneider, 2006) , equivocal findings with piracetam (Flicker and Grimley Evans, 2001) and there is no other evidence to support nootropics.
  • Other studies including RCTs of vitamin E and anti-inflammatory drugs have been negative.
  • There have been numerous trials conducted and ongoing in MCI due to AD or prodromal AD though none have been successful and progressed beyond Phase 3.

Other relevant issues in management

  • The National Institute for Health and Clinical Excellence (NICE) process.
  • There is also a NICE dementia guideline, GD42 (NICE, 2006), which was in the process of being fully revised at the time of the publication of this BAP guideline.
  • The current guideline recommends the use of ChEIs for Lewy body dementia, but not for FTD, VaD or MCI.

Perspective from a person with dementia

  • Many people with dementia and their carers have been important advocates for the clinical use of anti-dementia drugs and this should be an essential part of any decision making process.
  • His insights were invaluable and very much accorded with experience of the clinicians on the panel.
  • Peter reflected on the wider contexts in which the first prescription can be considered.
  • These range from the patient's initial interpretation of the significance of medication to the ethical imperative for professionals to strike a balance between the global quest for cure and the fundamental human rights of people with dementia for care and support.
  • This is consistent with the bio-psychosocial model of impairment which includes quality of life indicators.

SSRIs

  • There is type II evidence that SSRIs may help some behavioural aspects of frontotemporal dementia, but do not improve cognition.
  • Studies are mixed and further evidence is needed.

Treatment with cholinesterase inhibitors and vitamin E

  • There is type I evidence that cholinesterase inhibitors are not effective in reducing the risk of developing Alzheimer's disease and type I evidence that vitamin E is not effective in reducing the risk of Alzheimer's disease.
  • There is type 1 evidence that cholinesterase inhibitors are not effective in those with mild cognitive impairment A A profession carries the main responsibility for timely diagnosis and for maintaining the health and well-being of each person in their own homes for as long as possible.
  • It could also influence public opinion, politicians and the media by avoiding the use of degrading language involving time-bombs and tsunamis.
  • In their quest for prevention and cure, the authors have lost sight of the uniqueness of the individual highlighted by Tom Kitwood and more recently by Steven Sabat who focuses on the maintenance of a sense of self and personal identity from first diagnosis to the end of life (Schalock et al., 2016) .

The role of primary care in the management of dementia

  • Primary care general practitioners (GPs) increasingly work in larger multidisciplinary teams.
  • The contract links achievements in care quality, with a major focus on chronic illness care, properly funded through an evidence-based Quality and Outcomes Framework (QOF).
  • A UK pilot trial of a GP educational prescription to support dementia diagnosis and improve quality of care found that GPs had little knowledge of shared care protocols for anti-dementia drugs, with specialists still largely responsible for monitoring (Wilcock et al., 2013) .
  • New alternative primary care models with GP-led memory clinics and attached nurse facilitators have been established in some areas.
  • With regard to GP-led prescribing, this will be influenced by the revised NICE guidelines (due 2017); such a change in practice would however require upskilling of GPs, prescribing protocols and the development of a shared care, integrated system co-ordinated by possibly specialist nurses.

End of life care

  • One-third of older people will die with some form of cognitive impairment or dementia (Brayne et al., 2006) .
  • They may experience poor end of life care because they are often not perceived to have a terminal illness and health and social care services may not be optimally configured to meet their complex needs (Sampson et al., 2011) .
  • There is little evidence available on how best to prescribe for people with severe dementia, particularly when to stop drugs which are no longer necessary or beneficial.
  • In patients with moderate or severe AD, continued treatment with donepezil is associated with significant functional benefits over 12 months; thus continuing a ChEI may be in keeping with a palliative approach (level I evidence) (Howard et al., 2012) .
  • Covert medication may be in the person's best interests if conducted within the correct ethical and legal frameworks.

Other putative therapies for dementia

  • At the time of the previous guideline, a single randomised placebo-controlled trial (RPCT) of 183 people in Russia showed benefits of dimebon treatment over placebo (Doody et al., 2008) .
  • Unfortunately other studies have not been able to replicate these findings and a recent Cochrane review (Chau et al., 2015) concluded there was no beneficial effect of dimebon on cognition in AD, though did not rule out a possible benefit on behaviour.

Hormone replacement therapy (HRT)

  • A large primary prevention trial, the Women's Health Initiative Memory Study trial examined the possible benefit of HRT or estrogen replacement therapy (ERT) in reducing dementia in post-menopausal women (participants were 65-79 years at entry).
  • Adverse outcomes led to both arms being terminated early.
  • Following WHIMS the critical window hypothesis emerged claiming use of ERT in younger women might be beneficial but a recent review has questioned this and there is no good quality data to support this (Maki and Henderson, 2012) .

Withdrawal of anti-dementia drugs

  • There is type I evidence that continuing donepezil may decrease the rate of functional decline in moderate/severe dementia.
  • There is type III evidence that it may be inappropriate to prescribe memantine and cholinesterase inhibitors in advanced dementia towards the end of life.
  • C been proposed for preventing and treating dementia.
  • Whilst cross-sectional studies have generally supported this view (Ho et al., 2011) , prospective studies have not found a relationship between dementia and high homocysteine (Ho et al., 2011) and a systematic review of RCTs of B vitamin and folate supplementation found no beneficial effects on cognition in people with or without cognitive impairment (Ford and Almeida, 2012) .

Statins and dementia

  • No new RPCTs in relation to dementia prevention have been published since the last guideline.
  • Neither of the previous two large studies (heart protection study and PROSPER) found an effect of statins on ameliorating cognitive decline or dementia.

Therapeutic non-invasive brain stimulation

  • Interest in the use of non-invasive stimulation approaches such as transcranial direct current stimulation (tDCS) and rapid rate transcranial magnetic stimulation (rTMS) has gained significant traction over the past number of years.
  • Mechanistically both tDCS and rTMS modulate cortical activity non-invasively.
  • There was very little data to indicate whether any cognitive benefits are sustained.
  • In addition, it was noted in the meta-analysis by Hsu et al. (2015) that individual trial sizes were small and protocol designs heterogeneous; furthermore in the studies examined there was also evidence of positive publication although notably across the dementia studies which examined rTMS or tDCS there was a lack of any serious adverse events.

Disease-modifying therapies

  • There are several strategies currently being investigated for possible disease-modifying effects in people at high risk of progression to dementia, though most studies focus on AD and include subjects with prodromal AD or preclinical AD.
  • These include the use of drugs that may modulate amyloid and/or tau processing, e.g. to decrease production of beta amyloid or to increase its breakdown or removal, and other approaches which try to reduce the likelihood of amyloid monomers binding to produce oligomers and insoluble sheets.
  • There have also been anti-inflammatory and neurotrophic strategies.

Immunisation

  • The success of mouse vaccine studies led to the first human trials of an active Aβ 1-42 vaccine (AN1792) in people with AD.
  • Neuropathological examination of subjects from a phase I RPCT of AN1792 showed variable removal of amyloid plaques and no impact on long term clinical outcomes.
  • Aβ, failed to show overall clinical benefit in two large phase III studies of AD.
  • Unfortunately, this two-year RPCT study showed no efficacy on primary or secondary outcomes.
  • A number of these active or passive immunisation approaches are now being tested in long-term preventative RPCT studies of APOE e4 positive, cognitively normal subjects (CAD106) or presymptomatic carriers of early onset AD mutations (solanezumab, crenezumab and gantenerumab).

Folate and vitamin B12 for dementia

  • There is type I evidence that supplementation with folic acid with or without vitamin B12 does not benefit cognition in people with dementia.
  • On current evidence, neither vitamin B12 nor folate, either singly or in combination, can be recommended as treatments for dementia, or for dementia prevention.

Statins for the treatment or prevention of dementia

  • There is type I evidence that statins do not prevent dementia.
  • There is type II evidence that statins do not produce cognitive benefits in Alzheimer's disease.

B rTMS and tDCS

  • There is type II evidence indicating benefit of rTMS and tDCS on cognition but effects may not be sustained.
  • These treatments are not recommended until further evidence becomes available.
  • Epidemiological studies of the protective effects of NSAIDs are generally more positive.
  • Likewise a large randomised study of the NSAIDs naproxen and celecoxib in asymptomatic individuals with a family history of AD initially an increased risk of increased cognitive decline for both drugs.
  • Table 12 summarises recommendation strengths for disease-modifying therapies.

Optimising outcome measures for trials

  • Following the expansion of NHS Memory Services, the number of people diagnosed with dementia in the UK has increased hugely (Mukadam et al., 2014) , so that around 100,000 people per year receive a diagnosis of AD within the NHS.
  • These include early diagnosis, information, advance decision making, cognitive stimulation therapy, management of neuropsychiatric symptoms, strategies for family carers, ChEIs in AD, and changes in attitudes, including highlighting personhood and living well with dementia, but there is no cure or disease-modifying treatment for the common dementias (Prince et al., 2011) .
  • Currently trials of drugs for disease modification in AD use different outcomes e.g. magnetic resonance imaging (MRI) brain volume change or change in cognition or function.
  • They also use differing measures of the same outcome.
  • Use of an agreed set of the most valid trials' outcome measures for disease modification studies would improve efficiency and enhance interpretation of data across studies (Ghezzi et al., 2013) .

Prospects for prevention

  • Prevention is typically considered in three main subdivisions.
  • Secondary prevention is where clinical symptoms are prevented in people with evidence of disease, and tertiary prevention is where a later stage of clinical progression is prevented in people with both disease and symptoms.
  • As can be seen from this general description, the terms are dependent upon the definitions of 'disease' and 'symptoms'.
  • There are no drugs available that achieve secondary prevention of dementia (Schneider et al., 2014) .
  • Non-pharmacological, multi-modal interventions have shown better evidence of success than any drug to date e.g. the FINGER study (Ngandu et al., 2015) .

A Vaccination and immunisation studies

  • There is preliminary type II evidence of their effect in Alzheimer's disease on some endpoints, but also type II evidence that amyloid lowering does not affect clinical course.
  • Amyloid-lowering agents should not be prescribed until the optimal disease stage, safety and efficacy data are available.

Intervention Level of evidence Recommendation

  • Matthew Norton -declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
  • George McNamara -declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Did you find this useful? Give us your feedback

Figures (17)

Content maybe subject to copyright    Report

Citations
More filters
Journal ArticleDOI
TL;DR: The Lancet Commission on Dementia Prevention, Intervention, and Care met to consolidate the huge strides that have been made and the emerging knowledge as to what the authors should do to prevent and manage dementia.

3,826 citations

Journal ArticleDOI
TL;DR: The aim of this Review was to summarise the evidence regarding seven potentially modifiable risk factors for AD: diabetes, midlife hypertension, mid life obesity, smoking, depression, cognitive inactivity or low educational attainment, and physical inactivity.
Abstract: At present, about 33·9 million people worldwide have Alzheimer's disease (AD), and prevalence is expected to triple over the next 40 years. The aim of this Review was to summarise the evidence regarding seven potentially modifiable risk factors for AD: diabetes, midlife hypertension, midlife obesity, smoking, depression, cognitive inactivity or low educational attainment, and physical inactivity. Additionally, we projected the effect of risk factor reduction on AD prevalence by calculating population attributable risks (the percent of cases attributable to a given factor) and the number of AD cases that might be prevented by risk factor reductions of 10% and 25% worldwide and in the USA. Together, up to half of AD cases worldwide (17·2 million) and in the USA (2·9 million) are potentially attributable to these factors. A 10-25% reduction in all seven risk factors could potentially prevent as many as 1·1-3·0 million AD cases worldwide and 184,000-492,000 cases in the USA.

2,269 citations

Journal ArticleDOI
01 Jul 2018-Brain
TL;DR: The weight of the evidence supports the continued value of cholinergic drugs as a standard, cornerstone pharmacological approach in Alzheimer's disease, particularly as the authors look ahead to future combination therapies that address symptoms as well as disease progression.
Abstract: Cholinergic synapses are ubiquitous in the human central nervous system. Their high density in the thalamus, striatum, limbic system, and neocortex suggest that cholinergic transmission is likely to be critically important for memory, learning, attention and other higher brain functions. Several lines of research suggest additional roles for cholinergic systems in overall brain homeostasis and plasticity. As such, the brain's cholinergic system occupies a central role in ongoing research related to normal cognition and age-related cognitive decline, including dementias such as Alzheimer's disease. The cholinergic hypothesis of Alzheimer's disease centres on the progressive loss of limbic and neocortical cholinergic innervation. Neurofibrillary degeneration in the basal forebrain is believed to be the primary cause for the dysfunction and death of forebrain cholinergic neurons, giving rise to a widespread presynaptic cholinergic denervation. Cholinesterase inhibitors increase the availability of acetylcholine at synapses in the brain and are one of the few drug therapies that have been proven clinically useful in the treatment of Alzheimer's disease dementia, thus validating the cholinergic system as an important therapeutic target in the disease. This review includes an overview of the role of the cholinergic system in cognition and an updated understanding of how cholinergic deficits in Alzheimer's disease interact with other aspects of disease pathophysiology, including plaques composed of amyloid-β proteins. This review also documents the benefits of cholinergic therapies at various stages of Alzheimer's disease and during long-term follow-up as visualized in novel imaging studies. The weight of the evidence supports the continued value of cholinergic drugs as a standard, cornerstone pharmacological approach in Alzheimer's disease, particularly as we look ahead to future combination therapies that address symptoms as well as disease progression.

821 citations

Journal ArticleDOI
TL;DR: A better understanding of neuroimmune interactions during development and disease will be key to further manipulating these responses and the development of effective therapies to improve quality of life, and reduce the impact of neuroinflammatory and degenerative diseases.
Abstract: Neurodegenerative diseases, the leading cause of morbidity and disability, are gaining increased attention as they impose a considerable socioeconomic impact, due in part to the ageing community. Neuronal damage is a pathological hallmark of Alzheimer's and Parkinson's diseases, amyotrophic lateral sclerosis, Huntington's disease, spinocerebellar ataxia and multiple sclerosis, although such damage is also observed following neurotropic viral infections, stroke, genetic white matter diseases and paraneoplastic disorders. Despite the different aetiologies, for example, infections, genetic mutations, trauma and protein aggregations, neuronal damage is frequently associated with chronic activation of an innate immune response in the CNS. The growing awareness that the immune system is inextricably involved in shaping the brain during development as well as mediating damage, but also regeneration and repair, has stimulated therapeutic approaches to modulate the immune system in neurodegenerative diseases. Here, we review the current understanding of how astrocytes and microglia, as well as neurons and oligodendrocytes, shape the neuroimmune response during development, and how aberrant responses that arise due to genetic or environmental triggers may predispose the CNS to neurodegenerative diseases. We discuss the known interactions between the peripheral immune system and the brain, and review the current concepts on how immune cells enter and leave the CNS. A better understanding of neuroimmune interactions during development and disease will be key to further manipulating these responses and the development of effective therapies to improve quality of life, and reduce the impact of neuroinflammatory and degenerative diseases.

551 citations

Journal ArticleDOI
TL;DR: This revision of the 2005 British Association for Psychopharmacology guidelines for the evidence-based pharmacological treatment of anxiety disorders provides an update on key steps in diagnosis and clinical management, including recognition, acute treatment, longer-term treatment, combination treatment, and further approaches for patients who have not responded to first-line interventions.
Abstract: This revision of the 2005 British Association for Psychopharmacology guidelines for the evidence-based pharmacological treatment of anxiety disorders provides an update on key steps in diagnosis and clinical management, including recognition, acute treatment, longer-term treatment, combination treatment, and further approaches for patients who have not responded to first-line interventions. A consensus meeting involving international experts in anxiety disorders reviewed the main subject areas and considered the strength of supporting evidence and its clinical implications. The guidelines are based on available evidence, were constructed after extensive feedback from participants, and are presented as recommendations to aid clinical decision-making in primary, secondary and tertiary medical care. They may also serve as a source of information for patients, their carers, and medicines management and formulary committees.

475 citations

References
More filters
Reference EntryDOI
11 Jun 2013

113,134 citations

Journal ArticleDOI
TL;DR: The criteria proposed are intended to serve as a guide for the diagnosis of probable, possible, and definite Alzheimer's disease; these criteria will be revised as more definitive information becomes available.
Abstract: Clinical criteria for the diagnosis of Alzheimer's disease include insidious onset and progressive impairment of memory and other cognitive functions. There are no motor, sensory, or coordination deficits early in the disease. The diagnosis cannot be determined by laboratory tests. These tests are important primarily in identifying other possible causes of dementia that must be excluded before the diagnosis of Alzheimer's disease may be made with confidence. Neuropsychological tests provide confirmatory evidence of the diagnosis of dementia and help to assess the course and response to therapy. The criteria proposed are intended to serve as a guide for the diagnosis of probable, possible, and definite Alzheimer's disease; these criteria will be revised as more definitive information become available.

26,847 citations

Journal ArticleDOI
TL;DR: The workgroup sought to ensure that the revised criteria would be flexible enough to be used by both general healthcare providers without access to neuropsychological testing, advanced imaging, and cerebrospinal fluid measures, and specialized investigators involved in research or in clinical trial studies who would have these tools available.
Abstract: The National Institute on Aging and the Alzheimer's Association charged a workgroup with the task of revising the 1984 criteria for Alzheimer's disease (AD) dementia. The workgroup sought to ensure that the revised criteria would be flexible enough to be used by both general healthcare providers without access to neuropsychological testing, advanced imaging, and cerebrospinal fluid measures, and specialized investigators involved in research or in clinical trial studies who would have these tools available. We present criteria for all-cause dementia and for AD dementia. We retained the general framework of probable AD dementia from the 1984 criteria. On the basis of the past 27 years of experience, we made several changes in the clinical criteria for the diagnosis. We also retained the term possible AD dementia, but redefined it in a manner more focused than before. Biomarker evidence was also integrated into the diagnostic formulations for probable and possible AD dementia for use in research settings. The core clinical criteria for AD dementia will continue to be the cornerstone of the diagnosis in clinical practice, but biomarker evidence is expected to enhance the pathophysiological specificity of the diagnosis of AD dementia. Much work lies ahead for validating the biomarker diagnosis of AD dementia.

13,710 citations


"Clinical practice with anti-dementi..." refers background in this paper

  • ...The National Institute on Aging-Alzheimer’s Association (NIA-AA) group has published new criteria for AD dementia (McKhann et al., 2011), mild cognitive impairment due to AD (Albert et al....

    [...]

  • ...The National Institute on Aging-Alzheimer’s Association (NIA-AA) group has published new criteria for AD dementia (McKhann et al., 2011), mild cognitive impairment due to AD (Albert et al., 2011) and preclinical AD (Sperling et al., 2011)....

    [...]

Journal ArticleDOI
TL;DR: A conceptual framework and operational research criteria are proposed, based on the prevailing scientific evidence to date, to test and refine these models with longitudinal clinical research studies and it is hoped that these recommendations will provide a common rubric to advance the study of preclinical AD.
Abstract: The pathophysiological process of Alzheimer's disease (AD) is thought to begin many years before the diagnosis of AD dementia. This long "preclinical" phase of AD would provide a critical opportunity for therapeutic intervention; however, we need to further elucidate the link between the pathological cascade of AD and the emergence of clinical symptoms. The National Institute on Aging and the Alzheimer's Association convened an international workgroup to review the biomarker, epidemiological, and neuropsychological evidence, and to develop recommendations to determine the factors which best predict the risk of progression from "normal" cognition to mild cognitive impairment and AD dementia. We propose a conceptual framework and operational research criteria, based on the prevailing scientific evidence to date, to test and refine these models with longitudinal clinical research studies. These recommendations are solely intended for research purposes and do not have any clinical implications at this time. It is hoped that these recommendations will provide a common rubric to advance the study of preclinical AD, and ultimately, aid the field in moving toward earlier intervention at a stage of AD when some disease-modifying therapies may be most efficacious.

5,671 citations


"Clinical practice with anti-dementi..." refers background in this paper

  • ...The National Institute on Aging-Alzheimer’s Association (NIA-AA) group has published new criteria for AD dementia (McKhann et al., 2011), mild cognitive impairment due to AD (Albert et al., 2011) and preclinical AD (Sperling et al., 2011)....

    [...]

Journal ArticleDOI
TL;DR: These criteria for the diagnosis of vascular dementia are intended as a guide for case definition in neuroepidemiologic studies, stratified by levels of certainty (definite, probable, and possible).
Abstract: Criteria for the diagnosis of vascular dementia (VaD) that are reliable, valid, and readily applicable in a variety of settings are urgently needed for both clinical and research purposes. To address this need, the Neuroepidemiology Branch of the National Institute of Neurological Disorders and Stroke (NINDS) convened an International Workshop with support from the Association Internationale pour la Recherche et l'Enseignement en Neurosciences (AIREN), resulting in research criteria for the diagnosis of VaD. Compared with other current criteria, these guidelines emphasize (1) the heterogeneity of vascular dementia syndromes and pathologic subtypes including ischemic and hemorrhagic strokes, cerebral hypoxic-ischemic events, and senile leukoencephalopathic lesions; (2) the variability in clinical course, which may be static, remitting, or progressive; (3) specific clinical findings early in the course (eg, gait disorder, incontinence, or mood and personality changes) that support a vascular rather than a degenerative cause; (4) the need to establish a temporal relationship between stroke and dementia onset for a secure diagnosis; (5) the importance of brain imaging to support clinical findings; (6) the value of neuropsychological testing to document impairments in multiple cognitive domains; and (7) a protocol for neuropathologic evaluations and correlative studies of clinical, radiologic, and neuropsychological features. These criteria are intended as a guide for case definition in neuroepidemiologic studies, stratified by levels of certainty (definite, probable, and possible). They await testing and validation and will be revised as more information becomes available.

4,603 citations


"Clinical practice with anti-dementi..." refers methods in this paper

  • ...Cerebrovascular changes on imaging are necessary for the application of standard diagnostic criteria for VaD (Román et al., 1993), and increasingly imaging changes are being incorporated into other diagnostic criteria....

    [...]

Related Papers (5)