In this manuscript, we report the design as well as the clinical, neuropsychological and imaging characteristics of the experimental groups from the pilot E-ADNI study. We show the feasibility of the collection of clinical data, biological samples and MRI data within a European multicenter setting. Characteristics of the diagnostic groups are similar to the US-ADNI.
An important finding of this study is that the clinical features of the subjects recruited in the pilot E-ADNI were clinically comparable to those recruited the US ADNI. Despite subjects were approximately 5 years younger in the former group and notwithstanding some statistically significant differences, global cognitive function as assessed by the MMSE and CDR-SOB were only fractions of points different in the two studies, logical memory was also similar, and ADAS-cog total scores were never more than 2 points apart. To a certain extent, the observed similarity also applies to the results of the neuropsychological test battery, where some tests (clock drawing, trial making A, digit symbol, and Boston naming without cue) indicated systematically poorer performance in the US subjects and the category fluency 2 tests indicated poorer performance of only US MCI patients. While a consistent neuropsychological pattern cannot be identified, future ADNI efforts will need to specifically address the homogeneity of neuropsychological test administration and scoring with the US ADNI. These observations indicate that, despite the classification uncertainties surrounding the concept of MCI (8
), patients classified as “MCI”, in terms of global severity and to a certain extent of neuropsychological profile, are similar in European and US studies. The tendency to a difference in years of education between the US and Europe might at least in part be due to the different health coverage in the EU and US.
It is reassuring to note that a good quality 3D T1-weighted MRI scan was acquired for all 59 recruited subjects, supporting our choice to omit a routine repeat 3D T1-weighted sequence. However, the quality assessment consisted only of visual inspection, and detailed analysis of variations in signal-to-noise and contrast-to-noise ratios, and geometric distortion, using phantom data and data from travelling volunteers will follow. Because the sites of our study may be among those with the higher familiarity with high resolution sequences among those of the European Alzheimer’s Disease Consortium, and quality performance may decrease in a larger E-ADNI study. Omission of the routine repeat scan allowed an addition to the MRI protocol, consisting of DTI and rs-fMRI sequences. Analysis of this data is ongoing and will be reported elsewhere.
Structural MR features have been assessed with visual rating scales to explore disease effects. Although quick and easy, the scales we have used to rate MTA and subcortical cerebrovascular disease have been shown to yield good reliability and correlate well with hippocampal and white matter hyperintensity volume (9
). The distribution of scores in the pilot E-ADNI groups was as expected, with MTA increasing from controls to MCI patients to AD patients. WMH scores were similarly low among groups. Importantly, structural measures of MTA and WMH were not significantly different between the European and US groups, the measure closest to significance being right MTA score in controls (p=0.087). Although the criteria for the recruitment of our MCI patients were slacker than those of the US ADNI as we have been unable to carry out a strict centralized assessment of the diagnosis made by enrolling sites, it is good to see that cerebrovascular comorbidity of the European diagnostic groups is equally low, consistently with the expectation of enrolment of primarily degenerative cases.
It is interesting to note that the EU subjects seemed to have much lower comorbidity than their US counterparts, and this was true for all the assessed diseases (cardiovascular, respiratory, musculoskeletal, endocrine-metabolic, gastrointestinal, renal, and genitourinary) although with different degrees of statistical significance. The differences can hardly be explained by the marginally older age of US subjects and contrast with their higher educational attainment. The difficulty of achieving a satisfactory concordance of physical health assessment in multicentre clinical studies is a well know issue in the epidemiological literature (13
) that will need to be more thoroughly addressed in future ADNI efforts.
A few remarks on enrolment are warranted. The enrolment rate of the pilot E-ADNI sites was 2.8 subjects per month per site, implying that in order to recruit 800 subjects, as in the US ADNI, it would take 20 sites for 14.3 months or 40 sites for 7.1 months. Although this compares favourably with the US ADNI where enrolment has needed 60 sites for 12 months, it should be acknowledged that the pilot E-ADNI sites may be among the most performing, motivated and with more sophisticated technology among those of the EADC centres. Thus, the mean performance of a larger group of 20 or 40 sites might be lower than estimated based on performance of the present study. On the other hand, it is fair to acknowledge that due to budgetary restrictions nowhere among pilot E-ADNI sites has a large media campaign to favour patient and control enrolment such as that of the US ADNI been carried out.
The high proportion of patients as well as controls who successfully underwent lumbar puncture should be emphasized. The proportion of subjects accepting LP ranged from 68 to 83% in the European and 58 to 63% in the US groups, with the greatest difference in the controls (83 vs. 58%). While it is true that the subjects in this study have been recruited aiming to 100% CSF collection rate and we fell short of reaching that goal, while the US ADNI aimed at 20 and reached about 60%, it should also be recognized that subjects were enrolled in a reasonably short period of time, indicating that a larger European ADNI might achieve both a fast recruitment rate, and a reasonably high rate of lumbar punctures. On the other hand, our study did not include FDG PET, and had this been part of our protocol, the resulting burden of assessment to subjects might have led to a decrease of the rate of the proportion of lumbar punctures.
We conclude that by using the ADNI platform for clinical/neuropsychological and volumetric MR data collection, academic European Alzheimer’s Disease Consortium centres can enrol patients and controls similar to those of the US ADNI, and can collect CSF from a high proportion of subjects.