Neurology -- Correspondence for Rowe et al., 68 (20) 1718-1725

Correspondence published:

Imaging ß-amyloid burden in aging and dementia: G. Linazasoro MD (18 October 2007)

Reply from the authors: Christopher C. Rowe MD, Victor L. Villemagne MD, Colin L. Masters MD (18 October 2007)

Imaging ß-amyloid burden in aging and dementia 18 October 2007

G. Linazasoro MD,
Centro de Investigación Parkinson
Policlínica Guipúzcoa San Sebastián, Gipuzkoa, Spain
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Re: Imaging ß-amyloid burden in aging and dementia

glinazasoro{at}terra.es G. Linazasoro MD

I read with the article by Rowe et al with interest. [1] Diagnosing AD in a preclinical phase would enable early implementation of therapeutic interventions which might have long-term benefits.
PET technology by using the Pittsburgh compound (PIB) allows detection of amyloid deposits in the brain. [1,2] Pathological studies indicate that amyloid deposition is present in cortical regions of all patients with AD even before the onset of dementia. [3] One application of PIB-PET may be all that is necessary to identify the neuropathologic changes of AD in clinically normal individuals prior to the development of cognitive changes. These individuals would be considered to have preclinical AD.
PET studies performed with PIB in cognitively intact subjects have shown that between 15 and 22% of them had abnormal scans. [1,2] The objective is to determine who and when someone will become demented. It is and will be unclear because the proportion of subjects with cerebral amyloid deposits is, and will be, higher than the proportion of people suffering from clinical AD.
Otherwise, it is impossible to understand pathological observations which indicate that more than 30% of older persons over age 75 die without any clinical evidence of dementia despite showing amyloid deposits and pathological changes characteristic of AD.[3] Presumably all of them would have abnormal PIB-PET scans. Amyloid deposition is not synonymous with clinical AD unless we assume that everyone with an abnormal PIB-PET scan would develop AD.
Even in this case, many of them (70% according to pathological data and prevalence estimates of AD) will die without dementia in the preclinical stage of the disease. Alternatively, amyloid deposition could be an age-related phenomenon. [4] It is possible that the younger the age in which the deposition starts, the higher the possibility of eventually developing AD. Current studies indicate that none of the subjects with PIB-PET abnormalities was younger than 61 years-old. [1,2] Only one healthy person below the age of 73 showed abnormal deposits.
If neuroprotective therapy were available, early recognition of preclinical AD would allow a reduction of the likelihood of developing full dementia and eventually would lead to the disappearance of disabling AD. In the meantime, longitudinal studies are essential to determine the true predictive value of PIB-PET.
This also raises concerns about the informed consent process. There are negative consequences to misusing obtained information and limited value to performing costly studies because the final result can be anticipated (30% of people older than 70 will show abnormal PIB deposition). Similar situations are occurring in other neurodegenerative diseases. [5] In such studies, all possible scenarios should be discussed with candidates at the onset. Fully informed patients may participate provided the planned study is investigational (no personal results will be revealed), longitudinal and blind, with periodic clinical and neuroimaging evaluations to the whole group. Finally, participants would need to consent to donating their brains for clinical-pathological correlations. This is the only way to avoid ethical conflicts but implies a large, expensive study of more than 20 years of follow-up to have meaningful results.
Predictive testing with any tool not displaying a full predictive value can be harmful. We may have to rein in the technological imperative that urges, “if the technology exists, use it” by recalling that the objective is not what you can do but what you should do. PET studies are no exception.
References
1. Rowe CC, Ng S, Ackermann U, et al. Imaging beta-amyloid burden in aging and dementia. Neurology 2007;68:1718–1725.
2. Mintun MA, Larossa GN, Sheline YI, et al. [11C]PIB in a nondemented population: potential antecedent marker of Alzheimer disease. Neurology 2006;67:446–452.
3. Bennett DA, Schneider JA, Arvanitakis Z, et al. Neuropathology of older persons without cognitive impairment from two community-based studies. Neurology 2006;66: 1837–1844.
4. Braak H, Braak E. Frequency of stages of Alzheimer-related lesions in different age categories. Neurobiol Aging 1997;18:351–357.
5. Linazasoro G. Parkinson´s complex vs classical PD. Reflections against staging and in favour of heterogeneity. Eur J Neurol 2007;14:721-728.
Disclosure: The author reports no conflicts of interest.

Reply from the authors 18 October 2007

Christopher C. Rowe MD,
Austin Health Centre for PET
Melbourne, Victoria 3084, Australia,
Victor L. Villemagne MD, Colin L. Masters MD
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Re: Reply from the authors

Christopher.ROWE{at}austin.org.au Christopher C. Rowe MD, et al.

Dr. Linazasoro discusses the value of beta-amyloid detection in healthy elderly individuals. Dr. Linazasoro states that more individuals with cortical amyloid deposits die cognitively intact rather than with Alzheimer's disease.
Epidemiological and post-mortem studies suggest that both the prevalence of AD [6] and the finding of significant amyloid plaques in the general population [4,7] doubles every five years from the age of 60. However, asymptomatic plaques are present in individuals at double the prevalence of AD at the same age but equal to the incidence of AD 5-10 years later. This suggests a lag of up to 10 years between the appearance of AD lesions and the clinical diagnosis of AD.
Careful retrospective questioning often elicits a history of mild cognitive change predating diagnosis of AD by many years. [8] The prevalence of mild cognitive impairment (MCI) in the community is higher than that of AD [9] and may better match the presence of AD-type pathologic changes at a given age. In the recently commenced Australian Imaging Biomarkers and Lifestyle study of the elderly (AIBL), 150 healthy elderly subjects, 50 subjects with MCI and 50 with mild AD will have a PiB scan and psychometric review every 18 months.
Early analysis suggests that PiB binding in apparently normal elderly individuals is associated with mild impairment of episodic memory and correlates well with memory impairment in MCI. [10] It is vital to assess from such longitudinal studies what factors determine the rate of development of clinical AD. These factors may include the degree of PiB binding, age, level of education, co-existent cerebrovascular disease and ApoE genotype.
We agree that in the absence of an effective intervention, the value of a positive PiB scan in an apparently normal elderly individual is uncertain. Currently, we do not inform normal volunteers of their results. This may change when we further determine the factors that indicate if and when PiB positive subjects develop AD.
Currently, the clinical role of beta-amyloid detection, whether by PET scan or CSF measurement, should be to assist in the accurate diagnosis of AD in symptomatic patients with demonstrable cognitive impairment and differentiation of AD from frontotemporal dementia. Longitudinal multi-center studies are underway that will provide greater insight into the process of beta-amyloid deposition and its relationship to cognitive decline and ultimately its value as a preclinical predictor of Alzheimer’s disease.
In the meantime we await the development of effective intervention and utilize methods for early detection of beta-amyloid deposition.
References
6. Ferri CP, Prince M, Brayne C, Brodaty H, Fratiglioni L, Ganguli M, et al. Global prevalence of dementia: A Delphi consensus study. Lancet 2005; 366: 2112-2117.
7. Davies L, Wolska B, Hilbich C, Multhaup G, Martins R, Simms G, Beyreuther K, Masters CL. A4 amyloid protein deposition and the diagnosis of Alzheimer’s disease: prevalence in aged brains determined by immunocytochemistry compared with conventional neuropathlogic techniques. Neurology 1988; 38:1688-1693.
8. Amieva H, Jacqmin-Gadda H, Orgogozo J-M, Le Carret N, Helmer C, Letenneur L, et al. The 9 year cognitive decline before dementia of the Alzheimer type: A prospective population-based study. Brain 2005; 128: 1093-1101.
9. Di Carlo A. Lamassa M. Baldereschi M. Inzitari M. Scafato E. Farchi G. Inzitari D. CIND and MCI in the Italian elderly: frequency, vascular risk factors, progression to dementia. Neurology 2007; 68:1909-1916.
10. Pike KE, Savage G, Villemagne VL, Ng S, Moss SA, Maruff P, Mathis CA, Klunk WE, Masters CL, Rowe CC. â-amyloid imaging and memory in nondemented elderly individuals: Evidence for preclinical Alzheimer’s disease. Brain (In Press).
Disclosure: The disclosure on the article to which this correspondence refers indicates that GE Healthcare entered into an agreement with the University of Pittsburgh based on PIB. Co-authors of the article - Drs. W.E. Klunk and C.A. Mathis - are co-inventors of PIB and, as such, have a financial interest in this license agreement.