Serge Gauthier , MD , Christopher Patterson , MD , Howard Chertkow , MD , Michael Gordon , MD , Nathan Herrmann , MD , Kenneth Rockwood , MD , Pedro Rosa-Neto , MD, PhD , Jean-Paul Soucy , MD
McGill Center for Studies in Aging, Montreal, QC.DOI: http://dx.doi.org/10.5770/cgj.15.49
ABSTRACT
The 4th CCCDTD convened in May 2012 in Montreal with the primary aim of updating the previous diagnostic approach to AD, taking into account the revised diagnostic criteria proposed by the International Working Group (IWG) and the recommendations made by the National Institute on Aging—Alzheimer Association workgroups.
Key words: consensus , dementia , Alzheimer , diagnosis , imaging , symptomatic treatments
Since 1989, three Canadian Consensus Conferences on the Diagnosis and Treatment of Dementia (CCCDTD)(1,2,3) have led to evidence-based recommendations on the diagnosis and treatment of Alzheimer’s disease (AD) and related dementias. Previous CCCCDTDs have attempted to make recommendations relevant to health professionals of all disciplines treating dementia (e.g., primary care practitioners, as well as neurologists, geriatricians, and psychiatrists). Recommendations have been published in medical journals reaching out to a wide readership (such as the Canadian Medical Association Journal (CMAJ), as well as more specialized readership (such as the Canadian Journal of Neurological Sciences and Alzheimer’s & Dementia ). Following the last CCCDTD in 2006, the CMAJ published a series of case-based articles with recommendations for each stage of AD (asymptomatic at risk,(4) mild cognitive impairment,(5) mild to moderate dementia,(6,7) and severe dementia(8)).
The 4th CCCDTD convened in May 2012 in Montreal with the primary aim of updating the previous diagnostic approach to AD,(9) taking into account the revised diagnostic criteria proposed by the International Working Group (IWG)(10,11) and the recommendations made by the National Institute on Aging—Alzheimer Association workgroups (NIA/AA)(12,13,14) to which a Canadian perspective has already been published.(15)
The methodology of the meeting can be summarized as follows: The process was guided by the tenets of the AGREE collaboration to which 20 of the 23 criteria were met.(16) While previous CCCDTDs had used the evidence grading system developed by the Canadian Task Force on Preventive Health Care, for this iteration we attempted to follow, where possible, the GRADE system, in keeping with current recommendations for the conduct of consensus conferences.(17)
Complete background articles written by workgroups were posted to a password-protected website, accessible to all conference participants, who were encouraged to post comments. The recommendations, modified where appropriate as a result of participants’ comments, were then posted for online voting. Organizations relevant to the care of people with dementia were approached to appoint delegates. These delegates had full access to the background articles, were encouraged to comment, and were allowed to vote on recommendations. Online voting was closed one day before the conference assembly, which was held in Montréal on May 4th and 5th, 2012. At the conference, each topic was briefly reviewed before voting was carried out on each recommendation. All participants (except for the four industry observers) were permitted to vote. In the event of failed consensus, online votes of conference participants who were not able to attend the assembly were taken into account. As in each previous consensus conference, consensus was defined as 80% or more of conference participants voting for the recommendation. Partial consensus was defined as 60–79% of votes. Recommendations reaching consensus (≥ 80%) are listed in the tables of this article. Recommendations reaching only partial or no consensus are commented upon in the text. Strength of evidence is listed in the tables where possible. Recommendations clearly applicable only for research are flagged with “R” in the tables.
Most of the recommendations are particularly relevant to specialists treating patients with dementia because of the nature of the topics discussed: definitions/new diagnostic criteria for AD, use of neuroimaging and of liquid biomarkers, early onset dementia, and rapidly progressive dementia. Recommendations for these topics are therefore presented in this joint publication in key specialty journals in Canada: the Canadian Journal of Neurological Sciences and the Canadian Journal of Geriatrics . Symptomatic treatments, which are relevant to all treating physicians, are also reported in this article.
The motivation to revise criteria in Canada was the evolution of thinking about how dementia might be approached in light of new criteria in the United States. A proposal was made by the IWG led by Bruno Dubois and Howard Feldman to diagnose AD even before dementia has become manifest, using a specific clinical phenotype (memory impairment of the hippocampal type) and a biomarker.(10) In 2011, three workgroups of the NIA/AA recommended criteria for the diagnosis of dementia caused by AD,(12) MCI due to AD,(13) and asymptomatic AD.(14) These workgroups have embraced the Dubois/Feldman proposal in its reliance on biomarkers. In additional, the statement about vascular contributions to cognitive impairment (VCI) and dementia made by the American Heart Association/American Academy of Neurology(18) was also examined. Against this background, the CCCDTD4 recommendations are listed in Table 1.
TABLE 1
Recommendations regarding definitions of dementia, AD, and VCI
The practical messages are: (1) a recommendation in favor of the criteria for MCI due to AD, but to be used cautiously and only in specialized clinical practice; (2) a strong recommendation against the diagnosis of “prodromal AD” outside a research setting; (3) the recognition of the fact that an at-risk state for AD in asymptomatic persons should be made only in a research setting; and (4) the measurement of brain amyloid deposition using PET imaging in asymptomatic persons should be performed only in a research setting
In the context of an international effort to treat people who carry mutations for genes causing early onset familial AD,(19) and the requests for memory consultations for people in midlife, the issue of early onset dementia (i.e., prior to age 65) was examined. The recommendations outlined in Table 2 were approved by consensus of ≥ 80%.
TABLE 2
Recommendations regarding early onset dementia
The practical message is that patients with dementia starting before age 65 should be referred to a specialist, preferably in a clinical setting where genetic counselling and testing is available. The CCCDTD had recommended in 1999 that all such patients be referred to a specialist. The current CCCDTD recommends that even among specialists, referral should be made to colleagues with special expertise in this area.
In the context of increasing awareness of the many causes of rapidly progressive dementia (RPD), particularly Creutzfeldt-Jakob Disease, a mandatory reportable condition in Canada, the CCCDTD felt the need to define this condition operationally and suggested appropriate referral. Furthermore the common occurrence of rapid clinical decline in later onset dementia such as AD deserved a recommendation. The recommendations listed in Table 3 were approved unanimously.
TABLE 3
Recommendations regarding rapidly progressive dementia
The practical messages are: (1) patients with RPD where the diagnosis remains uncertain should be referred rapidly to appropriate specialty settings; and (2) patients with known AD who demonstrate faster-than-expected clinical decline should be reassessed for co-morbid conditions.
Neuroimaging was the most complex topic in this round of CCCDTD discussions. Reflecting the many technical advances in this area, the topic was operationally divided into an introduction with general recommendations, structural neuroimaging (CT and MRI), functional MRI, PET imaging (discussing both 18FDG and amyloid-binding ligands imaging), SPECT cerebral blood flow studies and MRI spectroscopy. Many of the recommendations are research related, since few of these tests are universally available for clinical implementation at this time. The issue of whether all patients with dementia should have structural imaging is debated at every CCCDTD conference, with the opinion that it is not required in all patients, but rather for those who have special clinical features (Table 4 from Patterson et al.(2)). One participant suggested that the age of 60 in that list was arbitrary and should be deleted. Participants voted against the recommendation that at least one structural imaging procedure should be done to establish the presence of clinically unsuspected cerebrovascular disease and to rule out potentially reversible structural etiologies in persons with cognitive impairment (26%). The recommendation that Health Canada approve the use of PET amyloid imaging in tertiary care dementia clinics did not reach consensus (63%). There was only partial consensus for the proposition that for a patient with MCI evaluated by a dementia specialist and in whom clinical management would be influenced by evidence of an underlying neurodegenerative process, an 18F-FDG PET scan be performed or, if not available, then a SPECT rCBF study be performed (72%) (see Tables 4 to 10).
TABLE 4
Recommendations from CCCDTD2 about CT scan needed if:
TABLE 5
Recommendations about FDG-PET and SPECT rCBF imaging
TABLE 6
Recommendations regarding structural imaging, CT, and MRI
TABLE 7
Recommendations regarding functional MRI
TABLE 8
Recommendations regarding PET amyloid imaging
TABLE 9
Recommendations regarding MR spectroscopy
TABLE 10
Recommendations regarding other neuroimaging modalities
The practical message is that structural imaging is not required in all (although will be indicated in most) persons with cognitive impairment. Although more costly and less available, MRI is preferable to CT. Where available, PET-18FDG and/or PET amyloid imaging can be used for clinical purpose in patients with atypical dementias.
In the context that cerebrospinal fluid (CSF) examination for Aβ42 and tau levels is a component of the biomarkers for AD in the IWG and the NIA/AA criteria, it was important to evaluate the feasibility and validity of CSF examination for routine diagnostic purpose or in atypical cases. Although everyone agreed that plasma Aβ42 are not reliable and are not recommended for clinical practice, the proposal that CSF Aβ42 and tau levels be measured did not reach consensus (64%), nor did the proposal that measures of CSF Aβ1–42, total tau and phosphorylated tau at ser 181 should be collected following a specific protocol and the quantification must be carried out by an experienced lab with a validated technology and continuous participation in quality control programs (71%).
The practical message is that, for now, measurement of CSF Aβ1–42 and tau have no clinical utility in Canada, although they are part of research protocols in observational and therapeutic studies.
Although there have been no new drugs approved in Canada or elsewhere since the CCCDTD3 meeting in 2006, it was considered important to review new evidence on the indications and best use of these drugs (Tables 12 and 13). Special emphasis was placed on discontinuation rules for cholinesterase inhibitors (CIs) which have not previously been clearly defined in the literature.
The practical messages are that: (1) concurrent causes of dementia have to be managed; (2) CIs are recommended for AD in mild to severe stages of dementia, AD with a cerebrovascular component, Parkinson Disease dementia, but not for probable vascular dementia; (3) the combination of CIs and memantine is logical, but an additive benefit has not been conclusively demonstrated; (4) for severe agitation the atypical antipsychotics risperidone, olanzapine and aripiprazole are recommended, but risks of therapy must be carefully weighed against potential benefits; (5) there is insufficient evidence for or against CIs, memantine, SSRIs, or trazodone as first-line therapy for neuropsychiatric symptoms; and (6) valproate should not be used for agitation and aggression.
Despite a large number of important advances, the CCCDTD4 concluded that fundamental changes in dementia diagnosis and management have not yet arrived. The IWG and NIA/AA AD criteria chiefly serve to codify standard practice in specialty settings for dementia and MCI due to AD, and for research at all stages of AD. As result, Canadian physicians who are not dementia experts will be little affected by the CCCDTD4 recommendations. The 1999 consensus recommended that younger patients (those < 65 years) and patients with rapidly progressive dementia be referred to dementia specialists and this has not changed, except that even among specialists in the disciplines to which such patients might be referred, tertiary referral of such patients should be made to colleagues with special expertise for that age group.
If the use of biomarkers becomes justified by further evidence, this will have implications for how cognitive decline is evaluated, and likely will have very substantial economic implications. Even now, Canadian physicians engaged in dementia research will need to consider how the new research criteria will impact their access to imaging modalities and laboratory tests that are not yet standard for dementia care in Canada.
TABLE 11
Recommendations regarding liquid biomarkers
TABLE 12
Recommendations regarding symptomatic treatments
TABLE 13
Recommendations regarding discontinuation of cholinesterase inhibitors
The authors declare that no conflicts of interest exist.
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Sincere thanks to the staff of Medplan who helped prepare the numerous teleconferences prior to—and the logistics of—the CCDTD4 meeting, as well as the staff of the McGill Center for Studies in Aging who helped during the meeting in Montreal.
*A. Al Rashed, R. Bartha, H. Bergman, J. Bethell, S. Black, C. Bocti, M. Borrie, A. Burham, C. Cook, J. Crowson, M. Donnely, H. Feldman, G. Heckman, D. Hogan, G.Y.R. Hsiung, G. Inglis, C. Jacova, R. Laforce, K. Lanctot, L. Lee, K. Leclair, M. Masselis, F. Massoud, A. Moore, S. Prasad, K. Rabheru, D. Sadovnick, L. Trudeau, I. Vedel, M. Williams ( Return to Text )
Canadian Geriatrics Journal , Vol. 15 , No. 4 , December 2012