The pathology of Alzheimer’s disease is present in the majority of cases of dementia. As the dominant or sole pathology, it accounts for over 50% of dementia, afflicting 5% of men and 6% of women over the age of 60 worldwide (World Health Organization 2002). However, the strength of the link between cognitive impairment and the pathological features of Alzheimer’s disease varies both with age and with each of the different pathological features. It has also been recognised that a significant number of individuals without clinical evidence of Alzheimer’s disease have amyloid deposition at death (Dickson 1992). Indeed, epidemiological neuropathological studies have established that there is no significant relationship between amyloid plaque burden and cognitive impairment in those over the age of 90 (Savva 2009).
The term 'Alzheimer’s disease dementia' (ADD) is used to describe those in whom the symptoms of cognitive impairment have progressed gradually to the point where the ability of the patient to perform everyday functions has been affected. Before this, there is a stage, known as mild cognitive impairment (MCI), in which the patient has a degree of cognitive impairment which is greater than expected for age, but is not impaired in function. Before MCI, there is a stage in which the pathology is present and increasing, but has not yet affected cognitive function, known as 'preclinical Alzheimer’s disease'.
MCI is a heterogeneous condition. In this protocol MCI refers to the clinical criteria defined by Petersen, or the revised Petersen criteria (Petersen 1999; Petersen 2004; Winblad 2004), or to the Cognitive Dementia Rating (CDR=0.5) scale (Morris 1993) or to the sixteen different classifications of MCI (Matthews 2008). There are four outcomes for those within an MCI population: progression to ADD, progression to another dementia, maintaining stable MCI, or recovery. At present, there is no clinical method to determine who, of those patients
The main concern of patients who present with worries about their cognitive function is whether there is a treatment which will either improve, or delay progression of their symptoms. The rate at which patients cross the boundary between preclinical Alzheimer’s disease and MCI, and between MCI and ADD, depends on several factors. Patients presenting to primary care are different from those in secondary care, who are different again from those in research settings. Those with ApoE4 genotype progress more rapidly. Within the 'MCI band', those with worse cognitive function progress more rapidly. Studies indicate that an annual average of 5% to 15% of MCI patients progress to ADD (Petersen 1999; Bruscoli 2004; Mattsson 2009; Petersen 2009).
Alzheimer’s disease pathology is associated with a central amyloidosis, and the presence of beta-amyloid plaques and neurofibrillary tangles in brain tissues at autopsy has been considered a 'gold standard' for the definitive diagnosis of Alzheimer’s disease (Mirra 1991; Winblad 1997; Newell 1999). However, Abeta amyloid plaques are present in conditions other than ADD (Villemagne 2008). Abeta amyloid deposits, measured with a 'Pittsburgh Compound-B' (PIB) radioactive substance, are higher in congophilic angiopathy (Johnson 2007) and dementias other than ADD. PIB retention and Abeta imaging in vivo could indicate more accurate differential diagnosis of the dementias. For instance, PIB could differentiate Alzheimer's disease from frontotemporal dementia (FTD) (Rabinovici 2007; Rowe 2007; Drzezga 2008; Engler 2008). The role of the PIB positron emission tomography (PET) biomarker in dementia differential diagnostics will be evaluated in a number of separate Cochrane systematic reviews.
It is a reasonable assumption, and one on which this review is predicated, that if a patient has both MCI and the pathology of Alzheimer's disease, and then goes on to develop clinical ADD, then the cause of the initial MCI and of the ADD was the Alzheimer’s pathology.
Our approach is an example of assessing diagnostic accuracy using 'delayed verification of diagnosis'. The distinction between 'prognosis' and 'diagnosis' is, in this circumstance, somewhat semantic. Instead of the reference standard being based on pathology however, it is based on a clinical standard: the progression from MCI to ADD or other dementias. Although, for the reasons stated above, this introduces a degree of unreliability, it has the advantage of being based on what matters to patients: progression.
The PIB-PET biomarker results represent Abeta amyloid deposition in the brain. We will be looking at the relation between 11C-PIB ligand binding in the brain and: i) conversion from MCI to ADD; or ii) conversion from MCI to other forms of dementia.
Target condition being diagnosed
In this review there are two target conditions: i) ADD and ii) other forms of dementia, which will be assessed at follow-up.
We will compare the index test results obtained at baseline with the results of the reference standards obtained at follow-up (delayed verification).
11C-PIB-PET test for the detection of Abeta amyloid deposition in the brain regions (e.g. the frontal, parietal and temporal cortices, posterior cingulum, etc.) at baseline.
11C-PIB-PET is a molecular imaging biomarker. PIB is a N-methyl-[11C]2-(4/-methylaminophenyl)-6-hydroxybenzothyazole radiotracer derived from thioflavin T (Klunk 2004). Price 2005 fully evaluated quantitative PIB-PET data in order to identify a valid, simple and reliable PET quantisation method for the routine measure of brain amyloid retention in vivo.
Dementia develops over 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 involved, and difficulty in planning complex tasks becomes increasingly apparent. In the UK, people usually present to their general practitioner, who may administer the index tests and refer the person to a hospital memory clinic. However many people with dementia do not present until much later in the disorder and will follow a different pathway to diagnosis, for example being identified during an admission to general hospital for a physical illness. Thus the pathway influences the accuracy of the diagnostic test. The accuracy of the test will vary with the experience of the administrator, and the accuracy of the subsequent diagnosis will vary with the history of referrals to the particular healthcare setting. Diagnostic assessment pathways may vary in other countries and diagnoses may be made by a variety of specialists including neurologists and geriatricians.
We are not including alternative tests in this review because there are currently no standard practice tests available for the diagnosis of dementia.
The Cochrane Dementia and Cognitive Improvement Group (CDCIG) is in the process of conducting a series of diagnostic test accuracy reviews of biomarkers and scales (see list below). Although we are conducting reviews on individual tests compared to a reference standard, we plan to compare our results in an overview.
CSF (Cerebrospinal fluid analysis of Abeta and tau)
sMRI (structural magnetic resonance imaging)
Neuropsychological tests (MMSE; MiniCOG; MoCA)
Informant interviews (IQCODE; AD8)
FP-CIT SPECT (Fluoropropil-Carbomethoxy-lodophenil-Tropane Single-photon emission tomography)
The new diagnostic criteria for Alzheimer’s disease and MCI due to Alzheimer’s disease (Dubois 2010; Albert 2011; McKhann 2011; Sperling 2011) incorporate add-on biomarkers based on imaging or CSF measures. These add-on tests to core clinical criteria might increase the sensitivity or specificity of a testing strategy. It is crucial that each of these biomarkers is assessed for its diagnostic accuracy before being adopted as a routine add-on test in clinical practice.
The 11C-PIB-PET biomarker, as the add-on test, might facilitate accurate identification of those patients with MCI who would convert to Alzheimer’s disease or other forms of dementia. At the present time there is no 'cure' for dementia, but there are some treatments which can slow cognitive and functional decline, or reduce the associated behavioural and psychiatric symptoms of dementia (Birks 2006; McShane 2006). In addition, the accurate early diagnosis of dementia may improve opportunities for the use of newly-evolving interventions designed to delay or prevent progression to more debilitating stages of dementia (Oddo 2004). Coupled with appropriate contingency planning, proper recognition of the disease may also help to prevent inappropriate and potentially harmful admissions to hospital or institutional care (NAO 2007).