Dementia is a syndrome of chronic and progressive cognitive impairment occurring in a setting of clear consciousness. It is due to underlying brain disease and impacts upon daily functioning to a significant degree. The ageing population will lead to an increased prevalence of neurodegenerative diseases presenting a huge socioeconomic burden with an annual estimated cost of currently over £17 billion in the UK.
Alzheimer's dementia is the most common dementia subtype, affecting 6% of individuals over the age of 65 and 20% over the age of 80 (Knapp 2007). In terms of prevalence, it is followed by vascular dementia, mixed Alzheimer's dementia/vascular dementia, dementia with Lewy bodies, alcohol-related dementia, frontotemporal dementia and then Huntington's disease (Lopes 2010).
In this review, the target condition is the differential diagnosis of Alzheimer's disease dementia from other dementia subtypes.
Alzheimer's disease is thought to underlie Alzheimer's disease dementia which is a clinical syndrome manifest as progressive memory decline with impairment in at least one other domain of cognitive function which impacts on the person's function and behaviour. Other non-neurodegenerative causes for the clinical syndrome e.g. tumour or stroke need to be excluded before the diagnosis can be made. Alzheimer's pathology affects the limbic system (primarily the hippocampus) and other mesiotemporal structures. The pathology also extends to other regions of the neocortex including the frontal and parietal lobes generating executive dysfunction and problems with praxis respectively. Over a period of 5 to 20 years the patient will develop worsening functional impairment as a consequence of their cognitive symptoms. Other dementias have other clinical features, for instance dementia with Lewy bodies principally leads to impairment in attention with prominent, early neuropsychiatric symptoms, frontotemporal dementias tend to affect planning, judgement, personality and language early and vascular dementia tends to follow a step-wise deterioration that is unpredictable in both speed of progression and clinical features. Current diagnostic criteria for these conditions rely predominantly on the clinical phenotype as opposed to biomarker abnormalities.
Vascular dementia is caused by underlying cerebrovascular disease (Burns 2005), and the diagnosis for probable vascular dementia is based on the National Institute of Neurological Disorders and Stroke and Association Internationale pour la Recherché et l'Enseignement en Neurosciences (NINDS-AIREN) criteria (Roman 1993), with 58% sensitivity and 80% specificity focusing on cerebrovascular disease consequences. These criteria are currently used for the differential diagnosis from Alzheimer's dementia in research settings.
Frontotemporal dementia, which is the second most common form of dementia in people below the age of 65 years, is a clinical syndrome associated with progressive change in personality, behaviour and language. Memory impairment is not a prominent feature but by late stage, multiple cognitive domains may be affected.
In Parkinson's disease dementia and dementia with Lewy bodies, the characteristic pathology responsible for neurodegeneration in vulnerable neuronal populations is the presence of α-synuclein and ubiquitin aggregates within intraneuronal inclusion bodies known as Lewy bodies. These consist of a dense granular core surrounded by a halo of radiating filaments. According to Braak's and McKeith's staging/categorisation systems the pathology correlates with clinical symptoms such that brainstem pathology is responsible for the extrapyramidal side effects whereas dementia results from neocortical pathology, thus Parkinson's disease and dementia with Lewy bodies are likely to form a continuum (Parkkinen 2008).
Dementia originating primarily from chronic alcohol abuse or secondarily by alcohol-related syndromes such as Wernicke's encephalopathy is also a common form of dementia in older individuals (Thomas 2001). The similarities between Alzheimer's dementia and ethanol-related neurodegeneration in addition to the higher prevalence of Alzheimer's disease dementia in older patients and enhanced reluctance to admitting alcohol abuse increases the requirement for differential diagnosis between these dementia subtypes (Kril 1999). The clinical diagnosis of 'alcohol induced persisting dementia', Kapaki 2005, is based on the criteria set out in the Fourth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV).
Sporadic Creutzfeldt Jacob disease and Alzheimer's disease share some clinical features as the former is characterised by promptly progressive dementia, implying the search for diagnostic tests for discrimination between the two disorders (Otto 2000). The International Statistical Classification of Diseases and Related Health Problems 10th Revision (ICD-10) clinical criteria such as clinical symptoms and characteristic electroencephalography (EEG) are used for diagnosis of Creutzfeldt Jacob disease including the presence of 14-3-3 protein in cerebrospinal fluid (CSF) (Van Everbroeck 1999).
In addition the discrimination of patients with dementia caused by normal pressure hydrocephalus from patients with Alzheimer's disease dementia or vascular dementia is important as dementia in normal pressure hydrocephalus is at the early stages considered surgically reversible (Kapaki 2007).
It can be seen therefore that dementia is a clinical syndrome that may have multiple aetiologies. Differentiating subtypes in clinical practice would, therefore, guide the clinician to optimal treatments as well as giving them the ability to convey prognosis and the risks to the off-spring of affected individuals. It is also the case that new treatments in development will be effective more specifically for dementia subtypes than is the case currently.
This review is concerned with the ability of the plasma and CSF amyloid beta protein 1-42 (Abeta42) tests in discriminating between Alzheimer's disease dementia and other dementia subtypes in patients already diagnosed with a dementia syndrome. These tests are the index tests, and they are relevant as they may reflect the underlying pathology of Alzheimer's disease. In this disease, a critical part of the pathological cascade is the aggregation of soluble Abeta42 into insoluble oligomers and then plaques. As plaques sequester soluble Abeta42 into plaque, there is an observable decrease in levels of Abeta42 in both plasma and CSF. These reductions have been clearly associated with Alzheimer's disease dementia but it is not clear if these changes are specific to Alzheimer's disease dementia or are a marker of other dementias too.
We will be comparing the index test results with the results of the reference standard, which is the clinical diagnostic criterion for Alzheimer's disease dementia. The use of biomarkers to differentiate between Alzheimer's disease dementia and other sub-types may be advantageous if it can replace lengthy clinical examinations or other more expensive tests, e.g. neuroimaging.
Target condition being diagnosed
Target condition in this review is Alzheimer's disease dementia.
Plasma and CSF Abeta42 levels
CSF serves as a good indicator of brain metabolism as it is in direct contact with the brain parenchyma (Le Bastard 2009). In Alzheimer's disease, Abeta aggregates to form plaques. These aggregates form from two species of Abeta being either 40 or 42 amino acids long. It is generally considered that Abeta42 is the more toxic species. This aggregation eventually culminating in the formation of plaque has the hypothesised effect of lowering CSF Abeta42 levels as there is the generation of a gradient between brain and ventriculo-subarachnoid space where Abeta passes to and from, respectively (Shoji 2002). This decrement in CSF Abeta relative to the increase in plaque formation is referred to as the amyloid sink hypothesis (Fagan 2006). There is less clarity with regards to the source of Abeta in plasma. Conflicting evidence suggests a decrease in plasma Abeta42 levels with an increase in Abeta40 levels, or a decrease in Abeta40 levels rather than Abeta42 levels for predicting Alzheimer's dementia (Sundelöf 2008, Van Oijen 2007). It is thought that the majority of Abeta measurable in plasma is derived from platelets. However, the interaction between CSF/Plasma/Brain compartments for Abeta has not been clearly articulated.
Previous work suggested that the CSFAbeta42/40 ratio, as opposed to Abeta42 levels in isolation, can differentiate between Alzheimer's dementia and other types of dementia including vascular dementia and dementia with Lewy bodies (Spies 2009). Moreover, CSF Abeta42 levels in frontotemporal dementia patients have been shown to be significantly higher than levels in Alzheimer's dementia patients (Riemenschneider 2002). Moreover, Abeta42 deposition in the striatum of dementia with Lewy bodies and Parkinson's disease dementia patients has been recently demonstrated, possibly leading to alterations in CSF Abeta42 levels in these conditions too (Mollenhauer 2006). Decreases in CSF Abeta42 levels have also been shown in Creutzfeld Jacob disease despite an absence of Abeta plaques; accordingly this alteration has been attributed to an alternative pathophysiological mechanism (Otto 2000). CSF Abeta42 levels have also been observed to be lowered in normal pressure hydrocephalus and alcohol related cognitive disorder patients (Kapaki 2005).
Dementia develops over a trajectory of several years. There is a presumed period when people are asymptomatic, and when pathology is accumulating. Individuals or their relatives may then notice subtle impairments of recent memory. Gradually, more cognitive domains become observably affected, and difficulty planning complex tasks becomes increasingly apparent. In the UK, people usually present to their general practitioner, who may refer to a specialist memory clinic. Our clinical question relates to later stages in clinical pathway, when people are already diagnosed with dementia. Prior to biomarker testing, patients included in primary research would have undergone clinical assessment in order to be classified as Alzheimer's disease dementia positive or Alzheimer's disease dementia negative participants; the Alzheimer's disease dementia negative participants would have undergone further clinical assessment and would have been diagnosed with the other dementia subtype (see 'Appendix 4'). The importance of the plasma and CSF Abeta42 biomarkers would be to differentiate between the Alzheimer's disease dementia and other forms of dementia, with the aim to treat each dementia subtype differently if/when possible. If CSF samples were to be used, due to their invasive nature, this would be the reserve of the specialist clinic.
We are not including alternative tests in this review because there are currently no standard practice tests available for the diagnosis of dementia. Although we are conducting reviews on individual tests compared to a reference standard, we plan to compare our results in an overview of reviews. The Cochrane Dementia and Cognitive Improvement Group is in a process of conducting a series of diagnostic test accuracy reviews of biomarkers and scales.
Positron emission tomography F-2-fluoro-2-deoxy-D-glucose (18F-FDG-PET);
Positron emission tomography Pittsburg Compound-C (11 C-PIB-PE);
Structural magnetic resonance imaging (sMRI);
Neuropsychological tests (e.g. Mini-mental state examination (MMSE); Mini-cognitive assessment (MiniCOG); Montreal Cognitive Assessment (MoCA))
Informant interviews (e.g. Informant Questionnaire on Cognitive Decline in the Elderly( IQCODE); The Washington University Dementia Screening Test, “Eight-item Interview to Differentiate Aging and Dementia” (AD8))
APOE e4 (Apolipoprotein E e4 variant)
Fluoropropil-Carbomethoxy-lodophenil-Tropane Single-photon emission tomography (FP-CIT SPECT).
The new diagnostic criteria for prodromal Alzheimer's dementia and Alzheimer's dementia incorporate and promote add-on biomarkers based on structural and functional imaging or CSF measures to improve diagnostic sensitivity and specificity (Albert 2011; Dubois 2010; McKhann 2011). These tests, added to core clinical criteria, might increase the sensitivity or specificity of a testing strategy. However, it is crucial that each of these biomarkers is assessed for their diagnostic accuracy before they are adopted as routine add-on tests in clinical practice.
The need for simple and accurate tests such as a blood test to accurately differentiate Alzheimer's disease dementia from other dementia subtypes may be effective and relatively easy in clinical practice. Moreover, it may enable the accurate identification of participants in clinical trials for testing the effectiveness of potential treatments specific for each dementia subtype.
However, the idea of this differentiation based on Abeta42 levels may not be relevant if it is shown that:
CSF Abeta42 levels are affected in all subtypes since this would support the use of treatments, which alter Abeta42 levels in all subtypes; or
patients are differentially diagnosed at a late disease stage reducing the possible therapeutic effectiveness of disease modifying drugs.
In view of this, the benefit of discriminating subtypes may be inversely proportional to the stage of illness. In early disease, discrimination may have major clinical benefit whereas in late stage disease, benefits of subtyping may be less relevant to the patients' management.