age-related cognitive decline, mild cognitive impairment or preclinical alzheimer's disease?

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R E V I E W A R T I C L E

Age-related cognitive decline, mild cognitive impairment or preclinical Alzheimer’s disease?

Pierre Celsis

With the promising development of effective treatment, significant improvement in the very early diagnosis of Alzheimer’s disease (AD) is required. There is vast agreement that a decline in memory, especially in verbal episodic memory, is the earliest and perhaps the most sensitive sign of incipient AD at the preclinical stage. However, this review offers evidence that impairment in episodic memory can be observed in normal elderly people as well as in aged subjects with mild cognitive impairment (MCI), a large proportion of whom will, however, not convert to dementia. Quantitative measurement of atrophy and brain activation in the hippocampal-parahippocampal formation by using structural and functional magnetic resonance imaging may help to distinguish the MCI decliners from the nondecliners. Cerebrospinal fluid levels of tau protein and AP,,, peptide, together with the presence of an apolipoprotein (apo)E ~4 allele may also increase our confidence in the early positive diagnosis of AD. This review concludes, however, that while adequate for constituting groups of patients in a research perspective, the extensive diagnostic procedure based on specific cognitive testing, neuroimaging and biological investigations is still out of reach for the practitioner.

Key words: age-related cognitive decline; Alzheimer’s disease; biological markers; brain imaging; genetic markers; hippocampal atrophy; magnetic resonance imaging; mild cognitive impairment; positron emission tomography; single-photon emission computed tomography.

Ann Med 2000; 32: 6-14.

Introduction

The ageing of our society has made the early and accurate diagnosis of Alzheimer’s disease (AD) an imperious necessity (1, 2). Indeed, establishing if possible the diagnosis at the preclinical phase of AD would be likely to increase the efficiency of treatment. The main difficulty in the early diagnosis of incipient AD is that the decline in cognition, which is considered the first symptom of the dementing process, is gradual and not easily distinguishable from the cognitive

From the Institut National de la Sant6 et de la Recherche Medicale, Unit6 455, and the Department of Neurology, Purpan University Hospital, and the University Paul-Sabatier, Toulouse, France.

Correspondence: Pierre Celsis, MD, PhD, INSERM, U455, Department of Neurology, CHU Purpan, 31059 Toulouse, France. E-mail: [email protected]. Fax: +33 5 61499524.

slowing often observed in aged individuals. In this review we report on some recent but now well- documented findings that may help the clinician in distinguishing preclinical AD from normal age-related cognitive decline and from mild cognitive impairment that may not progress to dementia. The article concludes with some comments on the present usefulness of the corresponding investigative procedures from the points of view of the researcher and the practitioner.

Normal agerelated cognitive decline

There is vast agreement between authors that the most prominent, and perhaps the only specific, age-related cognitive decline is a decrease in episodic memory performance (3, 4). The deficit, which manifests itself after the age of 70 years (4, 5 ) , predominates on learning and early retrieval, while retention is less

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MILD COGNITIVE IMPAIRMENT AND PRECLINICAL ALZHEIMER'S DISEASE 7

affected or not at all (4, 6). The memory performance is improved by semantic cueing, the efficacy of which is maintained in the oldest of the old (6). The decline is slow, and significant differences are usually not observed over a period as short as 2 or 3 years (7, 8).

Apart from episodic memory, deficits in other cognitive functions have been reported in normal ageing, although less consistently. These deficits would concern language skills (verbal fluency, naming and word comprehension), visuospatial abilities and executive functions, principally from the age of 80 years onward, while implicit memory and reading are preserved (3, 9). Subjects with higher education would be more resistant to changes in secondary memory and language, while education has no influence on attention and visuospatial abilities (3).

Incidence and prevalence of dementia and AlzheimerO disease in the elderly

From a recent prospective study on a large sample ( n = 2881) of aged subjects with a 5-year follow-up, Letenneur and co-workers calculated the annual incidence of dementia to be 1.3% for all causes of dementia and 0.97% for probable AD (10). The incidence varies with age and sex, from 0.23% per 100 persons per year in men aged 65-69 years to 6.6% cases per 100 persons per year in women aged 90 years or more. The global rate of incidence of AD is in agreement with the rate of 0.9% per year reported by Linn and co-workers (1 1) from a sample of 1045 subjects with a mean age of 72 years and confirms the figures obtained from previous studies of the PAQUID (Personnes AgCes Quid) cohort (12, 13). These incidence rates translate into a prevalence of dementia from all causes ranging from 4 4 % in subjects older than 65 years (11, 14, 15). The proportion of possible and probable AD being about 75% of all dementia cases (10, 14), the prevalence of AD can be estimated to be between 3% and 6%. It increases up to about 8% after the age of 70 years (16) and to about 12% in subjects aged 75 years or more (17).

The preclinical phase of Alzheimer's disease

In the past few years, several studies have tried to characterize the preclinical phase of AD, aiming at evidencing subtle cognitive deficits and at assessing their predictive value. The predictive value of the memory complaints has also received special attention.

A preclinical phase of AD exists that lasts for many years and is characterized by minor but detectable cognitive deficits (8 , 11 , 17, 18) . Emphasis has been

put on the deficit in memory, particularly episodic memory, as the earliest and most sensitive predictor of incipient AD (1 1, 19-22).

Other studies have shown that memory impairment is not the only deficit in preclinical AD. Naming, in particular, has been found impaired in some studies (8, 17), whereas it was found of no predictive value in a group of individuals at risk for familial AD (21). Dartigues and co-workers (12) showed that global cognitive performance, visual memory and verbal fluency were independent predictors of incipient AD, and Fabrigoule and co-workers (13), who used a principal component analysis and logistic backward regression on a set of cognitive tests, isolated a common factor that they interpreted to reflect the early disturbance of control processes in the preclinical phase of AD (for a recent review on attention, mental control and executive functions in early AD, see (23)).

It should be emphasized that, while the performance on cognitive tests may be predictive at the level of the group, the considerable overlap usually found between groups precludes any reliable individual diagnosis (8, 21).

Regarding the memory complaints, some authors consider that an isolated complaint is not predictive of the cognitive status, but is related to the affective state (24, 25). However, memory complaints accompanied with an objective memory deficit, or newly reported after having previously been denied, would be predictive of incipient dementia (26-28). A recent prospective study on a large sample, indeed, seems to indicate that memory complaints, especially when clearly expressed to the physician, constitute a risk factor for subsequent dementia (29).

The concept of mild cognitive impairment: diagnostic criteria, prevalence and conversion rate to dementia

Mild cognitive impairment (MCI) is presently the most widely used term for a concept that refers to nondemented aged persons with a mild memory or cognitive impairment that cannot be accounted for by any recognized medical or psychiatric condition.

Various diagnostic criteria have been proposed for the diagnosis of this condition: age-associated memory impairment (AAMI) (30), age-consistent memory impairment (ACMI), late-life forgetfulness (LLF) (3 1) and age-related cognitive decline (ARCD) (32), but it is out of the scope of the present review to report a detailed evaluation of these criteria, and for description, comparison and criticism we refer the reader for example to Hanninen et a1 (33) and Schroder et a1 (34). A consequence of the differences in the components of the diagnostic classifications and in the proposed norms is that large differences in the


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prevalence of the diagnosis can be observed. For example, the prevalence of AAMI between the ages of 60 and 64 years varies from 13.5% in the study by Schroder and co-workers (34) to 45.7% in the study by Koivisto and co-workers (35), the prevalence of ARCD in subjects over 60 years of age being around

However, a set of operationalized criteria seems to emerge from recently published works that may allow to delineate pragmatically the clinical and cognitive profile of patients with MCI (37-43). In addition to the usual exclusion criteria for dementia (44) and any other medical or psychiatric condition known to cause cerebral dysfunction, the set of criteria associates the existence of memory complaints documented by the patient or by a collateral source, a mildly abnormal score on global staging procedure, such as the Global Deterioration Scale (GDS = 2 or 3) (45) or Clinical Dementia Rating (CDR = 0.5) (46), a performance at 1.5 SD below age and education-matched controls on memory tests, and a score of at least 24 on the Mini- Mental State Examination (MMSE) (47) or 123 on the Mattis Dementia Rating Scale (DRS) (48).

Just as the prevalence of the diagnosis, the conversion rate of MCI to dementia greatly varies according to the criteria used. It ranges from quite low values of 1-2% per year when original AAMI criteria are applied to up to 20-30%0 for patients with a GDS of 3. In a number of studies cited above, however, the conversion rate converges to a value of about 12% per year. This rate is about 10 times higher than the incidence of dementia in the general population, as indicated above. MCI patients thus appear to be at high risk for subsequent dementia, and it is reasonable to postulate that a number of these patients are in the preclinical phase of AD.

However, not all the individuals with MCI will convert to dementia. This has been observed not only for patients fulfilling the AAMI criteria (49, 50), but also for more severely impaired patients selected according to more stringent criteria (39, 41, 43, 51, 52). All these studies reported that about 60% of the patients were cognitively stable over a period of 2-3 years.

We can thus conclude from these studies that MCI is a heterogeneous condition that includes decliners, ie patients who will convert to dementia, as well as nondecliners.

25% (34, 36).

Mild cognitive impairment: distinct cognitive profiles in decliners and nondecliners?

In patients with MCI, the severity of the deficit in episodic memory, especially verbal memory, has been found to be more pronounced in decliners than in

nondecliners (37-39, 43, 50, 53), a finding consistent with the reported high vulnerability of episodic memory processes in the preclinical phase of AD. For some authors, the retention would be particularly affected in decliners (39, 50), while for others the performance at immediate recall, not retention, discriminates decliners from nondecliners, especially when cued recall is used (38, 43).

Other cognitive functions, such as language (37) and more precisely verbal fluency (33) or naming (50) , have been reported to be more severely impaired in the MCI patients who will convert to dementia, compared with those with a stable deficit. A deficit in attention and executive functions has also been found to be an early and sensitive sign for predicting future decline in MCI (39,54) and also in subjects cognitively intact at inclusion (9), whereas orientation and short- term memory could also be of predictive interest in MCI subjects (52). However, the slight deficits in the cognitive functions mentioned above are difficult to evidence in MCI, and the distinction between decliners and nondecliners from their respective psychometric performance is not easy (21,43, 51).

Finally, the existence of different subtypes of decliners has been suggested by Ritchie and co- workers (3), who isolated two groups of subjects with distinctive cognitive profiles, the first one with preponderant impairment in language and implicit memory, the second one with predominant alteration of episodic and working memories.

To conclude, evidencing an impairment in verbal episodic memory would be insufficient to distinguish MCI from preclinical AD and normal age-related decline, as this function seems to be consistently impaired across the groups. Deficits in other functions such as language, attention and executive functions may be more distinctive but probably appear in a more advanced stage. Based on our knowledge of the normal ageing-related and abnormal pathological changes in brain tissues, additional markers for an early distinction must be found.

Neuropathological changes in normal ageing, mild cognitive impairment and preclinical Alzheimer's disease

Pathological alterations are frequently found in the brain of aged persons. According to Hulette and co- workers (55) 30-50% of nondemented subjects aged 75 years or more have pathological findings in the neocortex consistent with the diagnosis of possible AD and there is an age-related increase in neurofibrillary tangles (NFT), the distribution of which parallels that of AD (56).

However, recent studies have pointed to differences in the regional neuronal loss observed in the


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hippocampal-parahippocampal formation of normal aged subjects compared with AD patients. In nondemented aged subjects, a neuronal loss is observed in the subiculum (57, 58), while other subdivisions of the hippocampus seem less involved, and the entorhinal cortex is spared (59). In AD, the CA1 zone of the hippocampus and the entorhinal cortex, layers I1 and IV, show the greatest neuronal loss, the latter region evidencing a neuronal loss of 50% in patients with very mild AD (59).

The neuronal loss thus appears to be a more distinctive finding than NFTs for differentiating normal ageing from early AD. The presence or absence of a substantial neuronal death in the hippocampal- parahippocampal formation, especially the entorhinal cortex, may reflect a qualitative difference, ie structural versus functional impairment, between AD on the one hand and normal ageing or stable MCI on the other hand (60). In this perspective, it has been suggested that age-related memory impairment may be a consequence of a specific decrease in NMDA (N- methyl-D-aspartate) receptor levels of the hippocampal formation in the absence of extensive degenerative changes (60).

In AD, a staging model of neuropathological changes has been described based on the distribution of NFTs (61). This model distinguishes a transentorhinal stage, in which the NFTs are mainly located in the transentorhinal region, followed by a limbic stage with extension of NFTs to the CA1 cells of the hippocampus, and finally an isocortical stage, in which the isocortex is affected. Tentative matching of these neuropathological changes to the cognitive decline has been proposed (1 9), the transentorhinal stage being characterized by episodic memory deficits, the limbic stage by additional impairment in verbal abilities, visuospatial functions, attention and executive functions, while primary memory becomes affected in the isocortical stage.

Neuroimaging in the early distinction of Alzheimer's disease from normal ageing and mild cognitive impairment

Structural neuroimaging

With the introduction of magnetic resonance imaging (MRI), and especially of quantitative techniques, a number of recent studies have aimed at assessing the hippocampal-parahippocampal atrophy in normal ageing, its sensitivity in the early detection of AD and its predictive value in MCI.

In normal ageing, conflicting results regarding hippocampal atrophy have been reported. Jack and co-workers (62), examining a large group of 126 normal elderly subjects, found a significant linear decline in normalized hippocampal volume with

advancing age. Furthermore, longitudinal data in 24 subjects allowed these authors (63) to calculate the annual rate of atrophy. They found an annual average rate of hippocampal loss of about 1.5% with a significant predominance in the hippocampal head. On the contrary, Reiman and co-workers (64) found no significant correlation between hippocampal volume and age, neither in cognitively normal apolipoprotein (apo)E4 noncarriers nor in E4 homozygotes with a family history of AD. However, this study included small groups of relatively young subjects. Two other studies also failed to demonstrate a relationship between normal ageing and atrophy of the hippocampus (65, 66). These discrepant results suggest the use of age and sex-normalized scores of hippocampal atrophy, as done by Jack and co-workers (43), when comparing MCI or AD patients with aged controls.

In AD, the volume of the hippocampal-parahippocampal formation has been found to be consistently decreased compared with controls (65,67,68) even in very mild AD, in which the average hippocampal volume is 1.75 SD below the control mean and where 97% of the group have volumes below the 50th normal percentile (62). Furthermore, according to the authors the hippocampal atrophy appears independent of the apoE genotype (63), the former being a marker of the presence of AD, the latter a marker of the risk for it. In addition to the severity of the hippocampal loss, the annual rate of volumetric change was found to be about 2.5 times greater in AD patients than in controls (63). In the study of Juottonen and co- workers (68), the entorhinal cortex was the most severely affected part of the medial temporal structures in AD, confirming in vivo the results of Gomez-Isla and co-workers (59). Some studies have reported correlations between the hippocampal-parahippocampal atrophy in AD and impairments in memory components, verbal memory loss being related to the atrophy of the left hippocampus, while a visual memory deficit was associated with right amygdala and parahippocampal atrophy (69, 70).

In MCI, an early study by Soininen and co-workers (71) suggested the presence of minor changes in patients satisfying the criteria of AAMI, but a recent study by the same group (65) on a larger sample concluded that the hippocampal formation is spared in AAMI subjects. However, in MCI patients selected according to more appropriate age and education- matched criteria, a reduction of 14% in hippocampal volume was found by Convit and co-workers (67). The recent longitudinal study by Jack and co-workers (43), which makes use of a score normalized for age and gender and includes a large sample (n = 80) of MCI subjects, offers convincing evidence that hippocampal atrophy measured by rigorous quantitative MRI is predictive of conversion to AD, at least at group level. More precisely, this study shows that the

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smaller the hippocampal formation, the greater the rate of conversion to AD. Furthermore, the predictive value of the atrophy score remained significant independently of other factors such as the performance on psychometric tests or the apoE genotype.

Thus, from the studies above, an idea emerges that, while unable to clearly differentiate the heterogeneous MCI status from normal ageing, the quantitative measurement of hippocampal atrophy may distinguish the decliners from the nondecliners and may offer valuable help in the diagnosis of preclinical AD.

Functional neuroimaging

In normal ageing, there is a slight global decrease in cerebral blood flow and metabolism, which has been estimated by Petit-TabouC and co-workers to be approximately 6% per 10 years for the glucose metabolic rate (72). The distribution of changes is symmetric and without marked regional predominance.

In AD, a marked hypoperfusion or hypometabolism is observed, with regional disparities that contrast with the homogeneous pattern found in normal aged individuals. The predominance of alterations in the temporoparietal regions has emerged as the most sensitive and specific sign that distinguishes mild to moderate AD from normal ageing (73). The observed hypometabolism does not result from partial volume effects caused by brain atrophy, but reflects true metabolic reductions (74). The blood flow or metabolic pattern is related to the profile of cognitive impairment and may even announce subsequent neuropsychological changes in early AD (75, 76). It has also been shown to fit our neuropsychological knowledge on the impairment of the episodic, short-term and semantic memory systems (77).

In MCI, relative indices of parietal flow or metabolic reduction, especially hemispheric asymmetries, were more pronounced in apoE4 carriers (78) and predictive of subsequent dementia (53, 79, 80). In a recent study, however, McKelvey and co-workers (81), who used a nonquantitative, visual inspection of single-photon emission computed tomography (SPECT) images, found no predictive value for flow abnormalities in MCI subjects. According to Reiman and co-workers (64), who studied subjects a t genetic risk for AD (apoE4 homozygotes), the earliest and most sensitive sign would be a large reduction of glucose metabolism in the posterior cingulate cortex that precedes the decrease in hippocampal volume and the memory decline. Using sophisticated image processing and statistical analysis of SPECT data on a large control group and in 136 aged subjects who differed in degree of cognitive impairment, Johnson and co- workers (41) recently duplicated this finding.

In the past few years some authors have begun to apply brain activation imaging to the study of memory

processes in normal subjects, in elderly subjects with memory decline and in AD patients, with special interest in the medial temporal cortex response. Gabrieli and co-workers (82) showed the specific activation of the parahippocampal cortex during the encoding phase of episodic memory processes and the greater activation of the subiculum during retrieval. Comparing aged subjects with decreased performance in recognition memory with young controls, Grady and co-workers (83) found that the activations elicited in the right hippocampus and the left prefrontal and temporal cortices during encoding in young subjects were less pronounced in the aged, and that there was no evidence for functional compensation in old people.

Cardebat and co-workers (84) observed in AD patients a significant correlation between memory performance and blood flow increase in the right prefrontal cortex, a region that was not significantly activated in controls, possibly reflecting compensatory mechanisms. Finally, convincing evidence of the significance of task-induced changes in the study of memory decline and AD can be found in the data reported by Small and co-workers (85), who took advantage of the high resolution of the functional MRI technique. These authors showed two patterns of response in a group of elderly subjects with isolated memory decline. While the number of activated voxels was significantly decreased in the entorhinal cortex, the subiculum and the hippocampus proper of AD patients compared with controls, eight out of the 12 MCI subjects had a normal response in the entorhinal cortex and a significant decrease in the subiculum only, the four remaining subjects showing a pattern comparable to that of AD patients. These findings further support the notion that MCI subjects constitute a heterogeneous group including both predemented AD patients and non-AD subjects with memory- impairment. It should be stressed here, however, that functional neuroimaging with memory activation paradigms is a difficult technique that cannot be used as a clinical diagnostic tool at the moment.

Peripheral markers for the early diagnosis of Alzheimer's disease

Genetic markers

Aside of the mutations that confer a genetic risk for early-onset, familial AD, the ~4 allele of the apoE gene has been shown to convey an increased risk of developing early-onset AD (86). Therefore, the predictive value of the ~4 allele has been assessed for the preclinical detection of AD in healthy elderly persons and in subjects with MCI.

In the elderly population, Staehelin and co-workers (87) found a correlation between apoE genotype and episodic and semantic memory performance and


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processing speed. For Bondi and co-workers (22), the ~4 allele was related to poorer performance on delayed recall only, and as significantly more ~4 carriers than noncarriers developed dementia, the authors suggested that group differences in neuropsychological functions resulted from a higher prevalence of preclinical AD in the ~4 carriers rather than from a direct influence of the genotype on cognitive abilities. In cognitively normal individuals, Caselli and co-workers (88) found a negative correlation between age and delayed recall in the ~4 homozygotes only, suggesting that memory decline occurs earlier in this group, and Jack and co- workers (63) observed a nonsignificant trend towards smaller hippocampal volume in the ~4 carriers.

In subjects with MCI, there are converging results showing that ~4 carriers are at increased risk for developing AD (38, 39, 89), the apoE genotype being the best predictor of conversion to dementia for Petersen and co-workers (38), whereas for Tierney and co-workers (39) it is a reliable indicator only if memory performance is included in the predictive model.

Biological markers The search for biological markers of sporadic AD has been pursued during the past decade, aiming at ensuring the correct diagnosis while reducing the costs of the procedure. (2, 90, 91). Today, two promising candidates in the cerebrospinal fluid (CSF) may help establish a positive diagnosis of AD: the hyper- phosphorylated tau protein present in the NFTs and the AD,,, peptide of the neuritic plaque.

In normal ageing, the CSF tau level increases slightly but significantly with advancing age, whereas the mean level of CSF AD,,, is higher in older controls than in middle-aged subjects (92).

In AD patients, several studies have found an early increase in the tau level which remained stable over time and did not correlate with the severity of dementia (93, 94). The AD,,, level, which might be elevated in the early stage, has been found to decline with progression of the disease (95,96). Contradictory findings have been reported, however, showing that the tau level increased with progression of AD and correlated with the global cognitive decline (92), while the AD,,, level was stable during follow-up (97). Despite these discrepant results, the combined measurement of tau and AD,,, levels might improve the sensitivity and specificity of the early identification of AD patients (98).

Regarding MCI, no extensive study of the CSF tau and CSF AD,,, levels has, to our knowledge, been performed thus far. Hulstaert and co-workers (98) however, did include four MCI subjects in their study. Interestingly, these subjects showed increased tau and decreased AP,,, levels, as did AD patients. It remains

to be determined whether these subjects are MCI decliners in the preclinical phase of AD and whether nondecliners have normal tau and AD,,, levels.

To conclude, measuring the concentration of tau and AP,,, in the CSF may be helpful in the very early diagnosis of AD, but it should be stressed that in the works mentioned above the discriminative power was estimated from groups with established clinical diagnosis and that the individual predictive value of the tests is far from being ascertained.

Normal ageing, mild cognitive impairment and the prediction of Alzheimer‘s disease: concern for the researcher and burden for the practitioner

The way from a memory complaint alleged by the elderly patient consulting a memory clinic to the positive diagnosis of AD is not straightforward for the clinician, and indeed the diagnosis of MCI and the delineation of the ‘risk population’ is based on diagnostic criteria that differ largely between studies.

For the researcher, whose main concern is to improve the early diagnosis and to evaluate newly proposed therapies, this review shows, however, that substantial progress has been made allowing us to identify from the general elderly population subjects who are at high risk for developing AD. With regard to cognitive functions, impairment in verbal episodic memory appears to be a good predictor of incipient AD. However, as we have seen, episodic memory performance decreases with advancing age, and not all the subjects with mild but measurable memory impairment will convert to dementia. Thus, distinguishing preclinical AD from stable MCI cannot be based on memory testing alone, and other criteria should be used. In this respect, high resolution, quantitative MRI measurement of atrophy in different parts of the hippocampal and parahippocampal formation as well as memory activation studies of the medial temporal lobe with functional MRI may prove helpful in distinguishing MCI decliners from nondecliners. The potential usefulness of measuring the CSF levels of tau protein and AD,,, peptide for separating preclinical AD from stable MCI deserves further investigation. Finally, the presence of an apoE ~4 allele would increase the suspicion of sporadic AD.

For the practitioner, who is concerned by the individual early diagnosis of AD, the utility of such diagnostic procedures is not warranted at present. Indeed, all these diagnostic procedures have been evaluated on carefully selected groups with a high prevalence of disease. The cut-off points, hence the sensitivity and specificity, and the relative risk were determined from these samples. To achieve convincing evidence of practical usefulness, the true positive and


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negative predictive values of these tests should be established from new samples of consecutive patients not otherwise selected.

If the last requirement Were fulfilled, the availability of these procedures, especially those based on sophisticated imaging techniques, outside well-equipped and

specialized centres, notwithstanding their cost, will remain a pending question.

The author is grateful to Drs Alain Agniel, Dominique Cardebat, Jean-Franqois Demonet and Mich& Puel for stimulating discussions.

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