We found that the Neuroquant method distinguished patients with DAT from those without dementia who were assessed at a memory clinic. The method did not distinguish between patients with DAT and patients with other types of dementia. The diagnostic power is evaluated as of medium strength for distinguishing between patients with DAT and patients without dementia because the likelihood ratio for the best volumetric measurements was between 2 and 5 and the negative likelihood ratio was between 0.2 and 0.5.
Although the measurements for putamen and cortical grey matter were significantly different from AUC 0.5 in the comparison between patients with DAT and those without dementia (Table 3), this difference does not influence the diagnosis to any particular degree because the positive likelihood ratio was < 2. The same applies to the cerebellum, which was significantly different from AUC 0.5 in the comparison between patients with other forms of dementia and patients with DAT. We had expected the results of the ROC analyses of the age-standardised percentiles to be better than for structural volume (right + left)/intracranial volume of hippocampus, amygdala and lateral ventricles. They were not, and this may imply that these norms are not well enough validated and that they must be used with caution in clinical practice.
Our results are difficult to compare with earlier Neuroquant studies since positive and negative likelihood ratios are not reported in the latter (11) – (13, 15). The results are consistent with the results of studies where manual volumetric methods were employed and indicate that Neuroquant analyses are as good as far more time-consuming volumetric measurements (29, 30).
Better results than ours have been reported for some studies in which manual volumetric measurement was used. These are studies in which a comparison has been made between patients with DAT and healthy control subjects (31, 32). We would argue that the results of these studies are less relevant than ours, because a comparison between a diseased patient group and a healthy control group does not reflect the situation in clinical everyday life. In our study, none of the participants were healthy controls; they were all referred by their primary care doctor on suspicion of dementia.
About 50 % of those with mild cognitive impairment and 10 – 20 % of those with subjective cognitive impairment will develop dementia in the course of a five-year period (33, 34). Brain changes typical of Alzheimer’s disease start 10 – 15 years before the onset of clinical symptoms. This may mean that a number of our patients with mild cognitive impairment and subjective cognitive impairment have an early stage of Alzheimer’s disease even though they do not fulfil the criteria for dementia. This could be one explanation for the relatively low specificity we found for the brain structures (Table 3). Some of the patients in the group without dementia may be in the process of developing DAT and for that reason have atrophy of the hippocampus and amygdala and expanded lateral ventricles. It is more difficult to explain why a number of patients with the diagnosis DAT do not have typical MRI findings for this disease. One reason may be misdiagnosis. Nonetheless, surveys show that the consistency between a neuropathological diagnosis of Alzheimer's disease and the clinicians' diagnosis – DAT – is good, with a sensitivity approaching 90 % and a somewhat lower specificity (35).
The doctors who diagnosed the patients in this study are experienced, which should mean that misdiagnosis is not the primary cause of low sensitivity. A more probable explanation is that Alzheimer's disease does not always start in the entorhinal cortex, but in posterior cortical regions. Volumetric measurements in patients with this atypical development will not be affected in the same manner as they are in patients where the disease starts in the entorhinal cortex.
Our other main finding was that the Neuroquant analyses did not distinguish patients with DAT from those with other dementia diseases. This is not unexpected. According to neuropathological investigations, many patients with clinical dementia symptoms have a mixture of different types of dementia (36). Approximately 75 % of those with the diagnosis neuropathological dementia with Lewy bodies also have neuropathological changes in the brain that indicate concomitant Alzheimer's disease (37). The combination of vascular dementia, dementia with Lewy bodies and DAT is not uncommon either (36). It is possible that automatic MRI analysis would succeed in distinguishing DAT from frontotemporal dementia, but the group with frontotemporal dementia is too small to test this hypothesis. We have no answer to the question of why the cerebellum was significantly more atrophied in the group with other dementia diseases than in the group with DAT. This may be a random finding.
The study has weaknesses. We have used clinical diagnoses as the gold standard. This may introduce error, because a clinical diagnosis is never 100 % consistent with neuropathological diagnoses. On the other hand, neuropathological diagnoses are not a gold standard either (38). It can be argued that the clinical diagnostics would have been better if dementia markers had been measured in the spinal fluid of all the patients. But spinal fluid biomarkers are not a failproof means of identifying DAT either, or other dementia disorders. Many patients with normal values for tau protein and/or beta-amyloid have symptoms and disease progression consistent with DAT (4).
Another weakness is the inclusion of few patients with mild cognitive impairment and other types of dementia than DAT. In order to obtain definite answers to whether Neuroquant can be used in the differential diagnostic, far more patients with mild cognitive impairment, subjective cognitive impairment and different dementia diseases should be included in a similar study.
The strength of the study is the research design. Patients with competence to consent who were referred for dementia assessment were included continuously, a standard examination procedure was used for them all, and the results of the MRI quantification were not available to the doctors who set the diagnoses. Since more than half of the patients referred to the memory clinic in the period while the study was in progress were not included, it may be argued that the patients included were subject to a selection process. But this was not systematic selection; it depended only on whether the doctor providing treatment thought that the waiting time for the Neuroquant examination was too long.