British Journal of Radiology (2007) 80, S69-S70
© 2007 British Institute of Radiology
doi: 10.1259/bjr/12954578
Imaging the brain in dementia: expensive and futile?
A JACKSON, PhD, MBChB, FRCR, FRCP, FBIR1 and
N PURANDARE, MD, MRCPsych2
1 Imaging Science and Biomedical Engineering, The Medical School, University of Manchester, Oxford Rd, Manchester M13 9PT, 2 Psychiatry Research Group, School of Community Based Medicine, The University of Manchester, University Place (3rd Floor East), Oxford Road, Manchester M13 9PL, UK
Correspondence: A Jackson, Imaging Science and Biomedical Engineering, The Medical School, University of Manchester, Oxford Road, Manchester M13 9PT, UK. E-mail: alan.jackson{at}manchester.ac.uk
Dementia remains a clinical syndrome of progressive cognitive decline in multiple domains that can be caused by multiple aetiologies, with Alzheimer's disease and cerebral vascular disease being the two most common aetiologies. Dementia affects over 24 million people worldwide and, in keeping with the anticipated population growth, especially in older subgroups, the numbers are anticipated to double every 20 years to 81.1 million by 2040 [1]. The number of individuals affected with milder forms of cognitive impairment would be much higher.
In 1997, George et al [2] published a discussion document in the American Journal of Neuroradiology entitled "Imaging the brain in dementia: expensive and futile?". They identified the controversy that surrounds the use of high-cost diagnostic imaging techniques in view of the low diagnostic specificity and yield. They estimated that performing a single diagnostic MRI scan in every patient with dementia in the US would cost between $10 billion and $20 billion, giving an annual cost of up to $700 million for the next 35 years. Is this enormous expenditure justified in the face of shrinking health budgets? Many would argue that it is not and, in particular, that to "rule out another pathology" is an inadequate justification for the use of high-cost imaging modalities. Perhaps, in the clinical setting, a CT scan could be deemed adequate to exclude major treatable cerebral pathology. Another argument against the use of expensive diagnostic imaging modalities was the lack of effective treatments to halt or significantly modify the progression of dementia. However, the authors presented a number of arguments in favour of the use of routine cross-sectional imaging in dementia diagnosis. Their main argument was that routine clinical imaging of patients with memory and cognitive disturbances provided an enormous imaging data resource that improved our understanding of underlying diseases. In particular, they pointed to the increased understanding provided by imaging of the temporal progression of cerebral changes that occur early in the onset of Alzheimer's disease and thereafter during symptomatic progression. They emphasized that the recognition of normal pressure hydrocephalus as a potentially treatable form of dementia would not have been possible without the use of MRI. Finally, they discussed the increased understanding of the role of diffuse microvascular brain disease in patients with dementia, which has evolved from the observations of white-matter hyperintensities in the ageing brain on clinical MRI scans. The authors concluded that there is no choice but to image patients with dementia in order to "rule out unsuspected disease, rule in the most likely diagnosis and to continue to advance our understanding of the disease processes and their longitudinal progression".
Looking back on this discussion after 10 years, it is clear that the use of advanced cross-sectional imaging in the clinical assessment of dementia has grown enormously, in keeping with initial predictions. However, is there any evidence to support the suggestion that this has indeed "advanced our understanding of the disease processes and their longitudinal progression"? In this special edition of the British Journal of Radiology, we have asked a number of leading experts in the field of dementia imaging to review the current role and contribution of various imaging modalities to our understanding and clinical management of dementias.
It is striking that a great deal of imaging-based research continues to be focused on understanding the temporal progression of the diseases and identifying disease-specific patterns of brain involvement, usually characterized by atrophy. Several of our authors have identified the use of serial MRI as one of the most important methodological advances in the past 10 years (O'Brien; Schuff and Zhu; Sullivan and Pfefferbaum; Thompson and Apostolova; Scahill and Fox). There can be no doubt that, as a surrogate outcome measure, the ability to measure small changes in regional brain volume over periods of time as short as 1 year strengthens enormously the power of clinical trials of novel agents designed to combat the progression of Alzheimer's disease. However, the biological underpinnings of serial atrophy remain relatively non-specific, with similar atrophy rates in different disorders occurring as a result of different pathological processes. Furthermore, these techniques remain too complex for routine clinical use at the present time. Nevertheless, it is clear that the ability of cross-sectional imaging modalities to provide repeated non-invasive data have considerably improved our understanding of the causation and progression of dementia. This is particularly true in the difficult area of identifying ageing patients who are in the presymptomatic stages of Alzheimer's disease (O'Brien; Schuff and Zhu; Sullivan and Pfefferbaum). We have known for many years that early-stage Alzheimer's disease can be asymptomatic for a period of several years, often presenting with minimal cognitive impairment (MCI) characterized (usually) by memory dysfunction. Schuff and Zhu review characteristic imaging changes that have been described in patients with MCI. It is clear from their overview that our ability to measure serial changes in cerebral volumes has now been supplemented significantly by other advanced imaging techniques. The use of diffusion-weighted imaging to characterize pathological changes in white-matter has become an important part of the imaging armamentarium, with a broad range of disease-specific changes described in a number of white-matter pathways (O'Brien; Schuff and Zhu; Sullivan and Pfefferbaum). These studies have led to the increasing use of diffusion based white-matter tractography and, importantly, to attempts to quantify changes in specific white-matter tracts Molecular imaging techniques to identify changes in metabolic rate and blood flow, which are characteristic of specific disease states, and the development of targeted agents to identify molecular and cellular processes, such as deposition of amyloid, are increasingly showing promise, particularly in early-stage clinical trials (Herholtz et al; Pimlott and Ebmeier).
Another striking commonality between the articles included in this special edition is the emphasis placed on concomitant vascular disease as a significant contributor to dementia (O'Brien; Bronge and Wahlund; Knopman; Mills et al). In the late 1990s, there was a clear concept of dementias as primarily neurodegenerative or primarily vascular in aetiology. Vascular dementia was very much a catch-all diagnosis, encompassing any form of cognitive decline observed in patients with known cerebral vascular disease. In the past 10 years, the concept of vascular dementia as a single identifiable clinical entity has been challenged, and it is clear that a number of different vascular aetiologies can give rise to cognitive decline, often with distinctive clinical presentations. The best documented of these is normal pressure hydrocephalus (NPH). Our understanding of this disease has been greatly increased by the findings from functional MRI studies of the changes that occur in blood and cerebrospinal fluid (CSF) volume during the cardiac cycle. The identification and understanding of the Monroe–Kelly homeostatic mechanism has arisen entirely as a result of the ability of MRI to perform non-invasive gated studies of blood and CSF flow. This has led to revolutionary changes in our understanding of communicating hydrocephalus, which is now understood to result from increased cerebral capillary pulsatility. In NPH, reductions in the compliance cerebral arteries give rise to increased cerebral capillary pulsatility and transient changes in cerebral interstitial and ventricular CSF pressure, which are associated with variations in cerebral perfusion pressure. The combination of transient progressive ischaemia and associated ischaemic injury leads to a progressive decline in cerebral function, which can in some cases be reversed by shunting or ventriculostomy during its early stages (Mills et al). However, it is also increasingly clear that the distinction between neurodegenerative and vascular dementia is far less distinct than was once thought. There is now an extensive body of evidence, based on imaging, epidemiological and clinicopathological studies, that concomitant vascular disease is an important component in the causation and progression of dementia in patients with Alzheimer's disease, and that "mixed" dementia is probably the most common form of dementia in older people [3]. The challenge for the imaging modalities is to categorize and quantify the contributions of (micro and macro) vascular and neurodegenerative pathologies to help understand the clinical syndrome of dementia in an individual patient.
In conclusion, this series of reviews demonstrates major technical advances in both imaging and image processing that have greatly enhanced our understanding of the dementias. However, the power of these techniques remains most applicable in studies of the natural history of the disease and in clinical trials, rather than in widespread clinical practice. We could still present a coherent argument against routine use of high-cost imaging modalities in patients with dementia, but the arguments in favour of comprehensive imaging studies are now even stronger than they were in 1997. More importantly, the development of quantitative biomarkers based on imaging are likely to be amongst the most powerful tools available for the assessment of clinical efficiency in trials of novel therapeutic agents designed to slow or even prevent progression of neurodegenerative dementias.
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- Ferri CP, Prince M, Brayne C, Brodaty H, Fratiglioni L, Ganguli M, et al. Global prevalence of dementia: a Delphi consensus study. Lancet 2005. 366:2112–7.
- George AE, de Leon MJ, Golomb J, Kluger A, Convit A. Imaging the brain in dementia: expensive and futile? Amer J Neuroradiol 1997. 18:1847–50.
- Kalaria R. Similarities between Alzheimer's disease and vascular dementia. J Neur Sci 2002. 203–204:29–34.
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