Dementia: assessment, management and support: summary of updated NICE guidanceBMJ 2018; 361 doi: https://doi.org/10.1136/bmj.k2438 (Published 20 June 2018) Cite this as: BMJ 2018;361:k2438
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A large systematic review and network meta-analysis of 76 randomized controlled trials (RCTs) in 23,707 patients with Alzheimer’s disease revealed that no single drug or combination pharmacotherapy was effective when administered to patients with moderate-to-severe dementia.
Competing interests: No competing interests
Do CSF biomarkers and FDG PET imaging show sufficient clinical utility to support diagnosis of dementia subtypes? Re: Dementia: assessment, management and support: summary of updated NICE guidance
NICE recently published updated recommendations for diagnosing dementia and how people with this clinical syndrome navigate the care system. In this update, major changes from the previous version include the use of emerging diagnostic methods in research. NICE recommendations regarding the use of CSF biomarkers and FDG PET imaging for diagnosing dementia subtypes in specialist clinical setting are based on results from diagnostic test accuracy (DTA) studies identified and included in a systematic review conducted according to Cochrane DTA Handbook guidelines (http://methods.cochrane.org/sdt/handbook-dta-reviews). We have concerns about the way in which the evidence has been translated into practice recommendations.
At the level of basic science, the anti-amyloid beta protein (Aβ) antibody target  and cross-reactivity problems [2-3] have not been addressed in CSF biomarker research for measures of the ratio of Aβ(1-42/1-40). There is no standardisation of materials (including antibodies) or laboratory procedures to measure Aβ in biological fluids, leading to uncertain measures of different Aβ-type fragments. Procedures for performing the clinical assay for CSF biomarkers and cut off values for positivity need to be standardised and the reproducibility of the assay within and between laboratories needs to be assessed . These issues also apply for measures of CSF p-tau 181 and total tau.
According to the published NICE Dementia 2018 guideline , summarised in Pink et al 2018 , the rationale for recommendations on CSF biomarkers and 18F-FDG PET in specialist clinical setting is diagnosing dementia subtypes in people who are difficult to diagnose.
Combined CSF tau and amyloid beta biomarkers are ‘considered’ if Alzheimer’s disease (AD) dementia is suspected. However, the literature illustrates the accuracy achieved with a combination of amyloidosis biomarkers with neurodegeneration biomarkers are inconsistent and simply suggest that use of biomarkers might improve accuracy . While the NICE Committee acknowledged inconsistency of the results of combined CSF p-tau 181, and total tau and amyloid beta between studies [8-10] due to the mean age of participants amongst studies, it is important to highlight other sources that may lead to inconsistent and/or conflicting individual or combined biomarker results in diagnostic accuracy studies. These include: i) study design; ii) sample procedure and sample size; iii) participant characteristics; iv) different settings across specialist dementia services; v) variability in selected test abnormality thresholds (positivity); vi) variability in immunoassays for CSF biomarkers used, etc.
FDG PET imaging, as a measure of glucose metabolism, is ‘considered’ when AD dementia or Fronto-Temporal Dementia (FTD) is suspected, although it has been reported that FDG-PET is “less diagnostically informative for distinguishing AD from FTD” than for distinguishing AD from ‘other dementias’, ‘no dementia’ and ‘non-AD’. In addition, recent literature  suggests that FDG-PET pattern for FTD “can be more pervasive to most brain regions and can mimic AD”. Based on this evidence, we argue that differential diagnosis for dementia subtypes in ‘people who are difficult to diagnose’ in specialist clinical setting would still remain uncertain. Procedures for assessing typical AD pattern have not been standardised . There is insufficient evidence on the effect of covariates (age, APOE genotype, etc.) on hypometabolism in patients with AD pathology and a lack of studies that have compared the accuracy of different analysis approaches [7; 13].
Although amyloid PET imaging has been licensed for the UK use, NICE did not recommend this test to be ‘considered’ for the diagnosis of dementia subtype in specialist setting due to limited evidence available regarding the accuracy and cost-effectiveness. Instead, a research question: “Does amyloid PET imaging provide additional diagnostic value, and is it cost effective, for the diagnosis of Alzheimer’s disease and other dementias when compared with standard diagnostic procedures and other imaging or biomarker tests?” is recommended to be evaluated. However, the use of CSF biomarkers and 18F-FDG PET imaging are recommended, despite insufficient evidence that these diagnostic tests provide additional diagnostic value  or are cost effective for the diagnosis of AD dementia or FTD. This inconsistency suggests differential acceptance of limited evidence within the sub-disciplines of the dementia clinical community.
The recommendations incorporate suggestions which are not yet proven to be of value in the context of current diagnostic processes, particularly given the known complexity of dementia neuropathologically in the population. Research diagnostic criteria for Alzheimer’s disease dementia, incorporating these emerging biomarkers, have been put forward for use in research and highly specialised clinical research settings  but as yet the clinical validation of AD biomarkers does not meet the rigorous standards required for the translation from research to clinical settings [7; 16].
Despite these obvious evidence gaps and uncertainty in the scientific evidence, and without a consistent framework to assess clinical validity and utility of AD biomarkers, many memory clinics have already incorporated them into routine clinical practice on the assumption they inform assessment and management of patients. Their use has been heterogeneous and resulted in ‘informative’ values of biomarkers which certainly cannot be used with full reliability in clinical practice [7; 17]. This creep of insufficiently validated measures into clinical practice is not only expensive but also has ethical implications for those receiving the results.
What are the potential harms of implementing these diagnostic tests in the presence of this ambiguity? There is a significant risk of unnecessarily subjecting people with dementia to tests which do not yet have sufficiently evidenced diagnostic value for particular individuals taking into account age, gender and other key variables. The introduction of invasive and expensive biomarkers should be limited to those situations in which it is likely to make a meaningful difference to patient care. Specific differences in management that benefits individuals sufficiently to warrant these recommendations should also be clarified. Although it is recommended that these diagnostic tests should be ‘considered’, not ‘offered’, this subtlety is liable to be ignored in practice. Given the porosity of the boundary between dementia and MCI, there is likely to be substantial “diagnostic creep” here too.
The use of CSF biomarkers and FDG-PET imaging without detailed clinical guidelines based on high quality research evidence will lead to heterogeneous clinical practice. There is compelling need for rigorous research to validate individual and combined biomarkers with longitudinal clinical outcomes in different types of settings in which dementia diagnoses are made in order to fully reflect their usefulness in a variety of target populations.
In putting forward the recommendation to ‘consider’ the use of CSF biomarkers and FDG PET imaging for dementia subtypes based on variable quality of evidence, NICE is endorsing tests which have not yet shown sufficient clinical utility. By doing so NICE has not acknowledged the most recent literature, in which challenges to the use of these diagnostic tests in clinical setting are clear [5; 17]. The clinical guidelines must show greater clarity on the ambiguity in the knowledge base currently available.
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2. Crespi GA, Hermans SJ, Parker MW, Miles LA. Molecular basis for mid-region amyloid-beta capture by leading Alzheimer's disease immunotherapies. Sci Rep 2015; 5: 9649.
3. Hunter, S. and C. Brayne (2017). "Do anti-amyloid beta protein antibody cross reactivities confound Alzheimer disease research?" J Negat Results Biomed 16(1): 1.
4. Mattson N, Lonneborg A, Boccardi M, Blennow K, Hannson O, for the Geneva Task Force for the Roadmap of Alzheimer’s biomarkers. Neurobiology of Aging 2017;52:196-213
5. National institute for Health and care Excellence. Dementia – assessment, management and support for people living with dementia and their carers (NICE guideline NG97). 2018. www.nice.org.uk/guidance/ng97
6. Pink J, O’Brein J, Robinson L, Longson D, on behalf of the Guideline Committee. Dementia: assessment, management and support: summary of updated NICE guidance. BMJ 2018;361:k2438 doi: 10.1136/bmj.k2438.
7. Frisoni G, Boccardi M, Barkhof F, Blennow K, Cappa S, Chiotis K, Démonet JF, Garibotto V, Giannakopoulos P, Gietl A, Hansson O (2017) Strategic roadmap for an early diagnosis of Alzheimer’s disease based on biomarkers. Lancet Neurol 16, 661-676.
8. Toledo JB, Brettschneider J, Grossmna M, Arnold SE et al. CSF bimarkers cutoffs: the 21 importance of coincident neuropthological diseases. Act Neuropathol 2012;124:23-35.
9. Frisoni GB, Prestia A, Zanetti O, Galluzzi S, Romano M, Cotelli M, Gennarelli M, Binetti G, Bocchio L, Paghera B, Amicucci G,Bonetti M,Benussi L, Ghidoni R, Geroldi C. Markers of Alzheimer’s disease in a population attending a memory clinic. Alzheimers Dement 2009;5:307-317.
10. Dumurgier J, Schraen S, Gabelle A, Vercruysse O, Bombois S, Laplanche J-L, Peoc'h K et al. Cerebrospinal fluid amyloid-β 42/40 ratio in clinical setting of memory centers: a 32 multicentric study. Alzheimer's Research & Therapy 2015;7:30-38.
11. Shivamurthy VKN, Tahari AK, Marcus C, Subramaniam. Brain FDG PET and the diagnosis of dementia. AJR 2015; 2o4:W76-W85.
12. Frisoni G, Perani D, Bastianello S, Bernardi G, Porteri c, Boccardi M, et al. Biomarkers for the diagnosis of Alzheimer’s disease in clinical practice: an Italian intersocietal map. Neurobiology of Aging 2017;52:119-131.
13. Garibotto V, Herholz K, Boccardi M, Picco A, Varrone A, Nordberg A, et al. Clinical validity of Brain fluorodeoxyglucose positron emission tomography as a biomarker for Alzheimer’s disease in the context of a structured 5-phase development framework. Neurobiology of Aging 2017;52:183-95.
14. Boccardi M, Festari C, Altomare D, Gandolfo F, Orini S, Nobili F, Frisoni GB. Assessing FDG-PET diagnostic accuracy studies to develop recommendations for clinical use in dementia. J Nucl Med 2018;https://doi.org/10.1007/s00259-018-4024-1.
15. McKhann GM, Knopman DS, Chertkow H, Hyman BT, Jack CR, Jr., Kawas CH et al. The diagnosis of dementia due to Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimers Dement 2011;7:263-9.
16. Brayne C. A population perspective on the IWG-2 research diagnostic criteria for Alzheimer’s disease. Lancet Neurol. 2014 Jun;13(6):532-4.
17. Frisoni GB, Bochetta M, Chetelat G, Rabinovici GD, de Leon MJ, Kaye J, et al. Imaging markers for Alzheimer disease. Neurology 2013;81:487-500.
Competing interests: No competing interests
Like Dr Fisken (Responses, 8 July 2018), I was disappointed by the limited reference in the Pink et al (1) article to regular re-assessment of hearing loss in the management and support of people with dementia.
It is noteworthy that the recent NICE Guideline on Adult Hearing Loss(2) recommendations includes:
• 1.1.9 Consider referring adults with diagnosed dementia or mild cognitive impairment to an audiology service for a hearing assessment every 2 years if they have not previously been diagnosed with hearing loss.
Hearing loss has an estimated prevalence of 60% in the 70-79 year old age group and is almost ubiquitous beyond 80 (3), so the high incidence makes occurrence of new cases in people with dementia very likely. People with untreated hearing loss and no dementia easily become confused when trying to understand conversation.
There is also a Research Recommendation reflecting related developing concepts:
• In adults with hearing loss, does the use of hearing aids reduce the incidence of dementia?
Hearing loss affects cognitive ability in the absence of dementia. Cognitive Stimulation Therapy is recommended by the Dementia Guideline to promote cognition, independence and wellbeing. Hearing is a sense which exercises the brain particularly intensively, so its preservation is likely to be beneficial for all.
Awareness of the importance of hearing is vital when caring for people with dementia, and this deserves emphasising.
1. Pink J, O’Brien J, Robinson L, Longson D, on behalf of the Guideline Committee. Dementia: assessment, management, and support: summary of updated NICE guidance. BMJ 2018;361:k2438 (https://www.nice.org.uk/guidance/ng97)
2. Hearing loss in adults: assessment and management. NICE guideline (https://www.nice.org.uk/guidance/ng98)
3. Commissioning Services for People with Hearing Loss: A Framework for Clinical Commissioning Groups, NHS England (2016)
Competing interests: I have moderately severe adult onset hearing loss and am a volunteer with Action on Hearing Loss
The updated NICE dementia guidance on the subject of cognitive testing in primary care advocates use of brief validated tools, the specified instruments being the 10-point cognitive screener (10-CS) and the six-item cognitive impairment test (6CIT).1
As far as I can ascertain, there is only a single publication on 10-CS,2 hence no validation in independent patient cohorts. It may be a very good test, but pending further data it is difficult to understand how it can be recommended, other than on the basis of opinion of what constitutes good practice. Pragmatically, 10-CS has never been mentioned in referrals from primary care directed to this dedicated secondary care cognitive disorders clinic.3
The same cannot be said for 6CIT, which appears to be the most frequently used cognitive screening instrument in primary care in this catchment area, based on information in referrals made to this clinic. However, the negative scoring of 6CIT (higher scores worse) is associated with errors in scoring and reporting in about a quarter of referrals from primary care.3
The updated NICE dementia guidance finds no place for the General Practitioner Assessment of Cognition (GPCOG), although others have preferred it because it assesses recall and visuospatial skills, and incorporates an informant interview.4 GPCOG is frequently mentioned in referrals from primary care to our clinic, as is the MMSE.3
1. Pink J, O’Brien J, Robinson L, Longson D, on behalf of the Guideline Committee. Dementia: assessment, management, and support: summary of updated NICE guidance. BMJ 2018;361:k2438 (https://www.nice.org.uk/guidance/ng97).
2. Apolinario D, Lichtenthaler DG, Magaldi RM, et al. Using temporal orientation, category fluency, and word recall for detecting cognitive impairment: the 10-point cognitive screener (10-CS). Int J Geriatr Psychiatry 2016;31:4-12.
3. Cannon P, Larner AJ. Errors in the scoring and reporting of cognitive screening instruments administered in primary care. Neurodegener Dis Manag 2016;6:271-6.
4. Creavin S, Wisniewski S, Noel-Storr A, et al. Cognitive tests to help diagnose dementia in symptomatic people in primary care and the community. Br J Gen Pract 2018;68:149-50.
Competing interests: No competing interests
Re: Dementia: assessment, management and support: summary of updated NICE guidance, omission of Hearing assessments
Given that there is evidence that hearing loss may double the risk of developing dementia and may increase the severity of its effects, I was disappointed to note, in the section of your summary of the NICE guidance on 'Assessing and managing other long term conditions in people living with dementia' that there is no mention of the importance of initial and regular assessments of hearing function as well as eye tests in such people. This recommendation is in the full guidance and I am at a loss to understand why it has not been considered of sufficient importance to be included in your summary.
The estimated prevalence of hearing loss among people over 75 years of age is well over 50% and there is accumulating evidence that the earlier a person is assessed and fitted with appropriate hearing aids, the better able they are to adapt successfully and gain maximum benefit from them.
People with more severe dementia may find it more difficult to comply with standard audiometric procedures and it is therefore, surely, even more important that such hearing assessments are carried out as early as possible in the course of the disease.
I would be interested to read your response.
Competing interests: No competing interests