Evaluation of DSM-5 and IWG-2 criteria for the diagnosis of Alzheimer’s disease and dementia with Lewy bodies

Introduction

The recent publication of Second International Working Group for New Research Criteria for the Diagnosis of Alzheimer’s Disease (IWG-2) research diagnostic criteria has raised a number of important issues regarding not only Alzheimer’s disease (AD) but also dementia with Lewy bodies (DLB). Although these criteria are ostensibly for AD, their inclusion of Lewy body disease in mixed AD, means they also impact on DLB diagnosis.

Diagnostic criteria for both AD and DLB have undergone considerable revision over the past decade [1–4]. However, it is DLB in particular that continues to present problems with a recent publication questioning our ability to diagnose this condition [5]. Despite fewer difficulties with diagnosis, AD diagnostic criteria have been revised to include the use of biomarker identification in order to facilitate earlier diagnosis, hopefully eventually permitting treatment prior to extensive neurodegeneration [3]. Therefore, following the recent publication of fifth edition of the diagnostic and statistical manual of mental disorders (DSM-5) diagnostic criteria [6], both DSM-5 and IWG-2 [1] provide revised criteria for the diagnosis of AD. Comparison between DSM-5 and IWG-2 needs to be tempered by awareness that each of these sets of diagnostic criteria have different target audiences; the former aimed at clinicians, the latter intended for use in research settings [6, 1]. Nevertheless comparison between these two sets of criteria is possible due to cross-application recommended by the authors of both DSM-5 and IWG-2: the preface to DSM-5 states that these criteria can be used “as a reference for researchers” [6], and IWG-2 criteria discuss possible future clinical application, particularly to diagnose young-onset and atypical AD [1]. It is important to note it is likely that Dubois et al. [1] probably intend young-onset to refer to the extremely small number of cases of AD caused by highly penetrant genetic mutations [7], despite the vast majority of young-onset AD being sporadic [8].

By examining and comparing DSM-5 and IWG-2 diagnostic criteria (see Table 1), it is intended that a realistic appraisal of their relative merits in both clinical and research settings will be determined. For example, the clinically oriented DSM-5 may be adequate and sufficient for the diagnosis of both AD and DLB. However, in the future IWG-2 may have a meaningful contribution to make towards diagnosis of AD and DLB in both research and clinical settings.

Table 1

DSM-5 and IWG-2 criteria for the diagnosis of Alzheimer’s disease and dementia with Lewy bodies.

CSF biomarkers

The cerebrospinal fluid (CSF) biomarkers amyloid beta peptide consisting of 42 amino acids (Aβ₄₂) and tau are not only useful aids in the identification of AD but more importantly are a means of detecting the earliest signs of this disease. However, their clinical utility requires effective treatment applied in early stage AD prior to irreversible neurodegeneration. Although not available at present, it is hoped effective treatment will be available in future. At present there is extensive evidence for decreased Aβ₄₂ concentrations together with elevated total and phosphorylated tau (T-tau and P-tau) indicating which patients are more likely to progress to AD [9–14]. A recent review found CSF biomarkers differentiated AD patients from healthy controls with specificity and sensitivity of 80%–90% [11]. Furthermore, combined analysis of both biomarkers has consistently been found to improve both sensitivity and specificity of detecting AD [12]: although a combination of decreased Aβ and increased tau improved sensitivity only marginally (from 78%–84% to 86%), specificity was found to improve markedly (from 84%–90% to 97%) [11]. It has even been suggested that CSF biomarkers may eventually replace autopsy results as the gold standard for diagnosis of AD. [15]. However, questions remain as to whether this evidence is sufficient and it is frequently asserted that full validity has not been established [6, 16, 17]. Irrespective of the validity of CSF biomarkers, current American Academy of Neurology practice guidelines do not recommend routine analysis of CSF to evaluate biomarker proteins [18, 19].

However, given the restricted availability of both lumbar puncture and CSF analysis the validity of CSF biomarkers may be academic for everyday clinical diagnosis of AD, even in the future restricted to “expert centres with adequate resources” [1]. Furthermore, the invasive nature of CSF collection, and other issues such as culture and cost, deters some patients from consenting to this procedure 2]. Extremely pertinent to the use of CSF biomarkers in routine clinical practice is the success of clinical diagnosis of AD in the absence of biomarker information. A clinical diagnosis of AD is confirmed at autopsy approximately 90% of the time [16] rendering further invasive investigation redundant.

Mixed AD

The earlier decision by Dubois et al. [3] to reject a diagnostic category of “mixed AD” was based on the presence of comorbid disease that is not the cause of the dementia, and reducing the chance of a patient fulfilling the criteria for more than one diagnostic category. Dubois et al. [1] includes mixed AD as a diagnostic category consisting principally of cerebrovascular disease and DLB. The change in perspective by these authors was foreshadowed by their revised definition of AD [4] which specifically addressed the issue of multiple etiology. Dubois et al. [4] provided diagnostic criteria recognizing that the presence of “multiple disorders does not equate to proof of multiple causation”. In the case of DLB this consisted of the presence of extrapyramidal signs, visual hallucinations and cognitive fluctuation together with Dopamine transporter single photon emission computed tomography (DAT SPECT). This focus on aetiology overcomes the first objection to a mixed AD diagnostic category and may address the second objection by reducing the chance of a patient fulfilling more than one diagnostic category. Dubois et al. [1] acknowledge the challenges confronting recognition of mixed pathology in clinical diagnosis, again suggesting that a combination of clinical features and biomarker evidence is sufficient to indicate multiple aetiology and confirm a specific comorbid disease is, together with AD, a cause of the dementia.

McKeith et al. [2] addresses the issue of a combination of AD and DLB pathology, concluding that in individual cases the proportion of one to the other is inversely related to diagnosis. For example extensive Alzheimer’s type pathology (ADTP) reduces the likelihood of a diagnosis of DLB. This information and approach recognizes the occurrence of mixed AD/DLB pathology but decreases the necessity for a “mixed AD” diagnostic category. On the contrary, the third report of the DLB consortium [2] delineates diagnostic criteria for DLB that contribute to studies showing that “clinical diagnostic accuracy for DLB is higher in patients with low burdens of AD-type pathology” thereby contributing to research distinguishing this condition from AD. Furthermore, the coexistence of AD and DLB pathology is very common with the majority of cases of both conditions having mixed pathology [1, 20, 21]. Therefore, since most cases of AD are mixed AD and most cases of DLB are mixed DLB, it is impractical to have a separate “mixed” category. Dubois et al. [1] include the core features of DLB in their category of mixed AD with Lewy body disease together with dopamine transporter positron emission tomography (DAT PET). There is no specific mention of progressive cognitive decline which according to McKeith et al. [2] is a mandatory feature of DLB. However, this may be because Kraybill et al. [22] found that DLB alone has more severe impairment of executive function than a mixture of AD and DLB equivalent to Dubois et al.’s [1] mixed AD. Impaired executive function and attention being the predominant early expression of cognitive decline but usually appearing somewhat later in AD [1]. Consequently, it is possible progressive cognitive decline may be inferred given the common occurrence of this clinical feature in both AD and DLB. A further objection to a separate diagnostic category of “mixed AD” is that a preponderance of either ADTP or Lewy body pathology makes a diagnosis of DLB or AD, respectively less likely [2] indicating that each diagnosis resides at either end of a single continuum affirming standard neurological procedure of diagnosis by preponderance of signs and symptoms.

Conclusions

It is doubtful that the addition of largely unavailable and not fully validated diagnostic tests included in IWG-2 criteria outweigh the practical value of the diagnostic criteria listed in DSM-5 [6] for the diagnosis of AD. Furthermore, inclusion of a “mixed AD” category seems to add to the confusion surrounding the diagnosis of DLB as opposed to DSM-5 [6] criteria replicating the third report of the DLB consortium [2]. However, it is possible that future advances may solve these issues and eventually lead to regulatory qualification and approval for IWG-2 diagnostic criteria. Although IWG-2 [1] is superior for identifying preclinical and prodromal indicators of ADTP due to the use of a specific combination of well-evidenced CSF biomarkers (Aβ₄₂ and P-tau or T-tau), it may be some time before these criteria gain approval for general clinical use.