Elsevier

The Lancet

Volume 348, Issue 9020, 13 July 1996, Pages 94-97
The Lancet

Early Report
Visualisation and quantification of rates of atrophy in Alzheimer's disease

https://doi.org/10.1016/S0140-6736(96)05228-2Get rights and content

Summary

Background

Definitive diagnosis of Alzheimer's disease requires histological examination of brain tissue. In life, brain atrophy can be visualised by computed tomography or magnetic resonance (MR) imaging, but the atrophy due to the disease is difficult to distinguish from that caused by normal ageing. We have investigated use of accurate positional matching (registration) and digital subtraction of serially acquired MR brain scans to allow determination of rates of global and regional atrophy.

Methods

This technique was applied to eleven patients with clinically diagnosed Alzheimer's disease and eleven age-matched controls. Each individual had two scans approximately 1 year apart; scan intervals were matched between the groups.

Findings

The median rate of atrophy was significantly greater in the Alzheimer's disease group than in the control group (12·3 [range 5·8 to 23·6] vs 0·3 (−1·2 to 1·7) mL per year; p<0·0001). There was no overlap between the groups. Furthermore, three non-demented individuals at risk of familial Alzheimer's disease had scans 6–14 months apart and showed greater rates of volume loss than the controls; these three individuals have subsequently developed symptoms.

Interpretation

This technique may be useful for the diagnosis of Alzheimer's disease, the assessment of disease progression, and the evaluation of potential treatments.

Introduction

A definitive diagnosis of Alzheimer's disease relies on histological confirmation of sufficient numbers of amyloid plaques and neurofibrillary tangles. Although these histological features cannot be examined non-invasively, the cell loss that accompanies them can be seen in vivo as atrophy on computed tomography (CT) or magnetic resonance (MR) brain scans.1, 2, 3, 4 Radiological evidence of atrophy supports a clinical diagnosis, but because of the wide normal variation in cerebral structures distinction of atrophy associated with Alzheimer's disease from normal ageing is difficult in the early stages of the disorder.4, 5, 6, 7, 8, 9, 10 Most investigations with MRI or CT to quantify atrophy involved manual measurements of specific structures thought to be most affected in Alzheimer's disease (eg, hippocampus, amygdala, temporal lobe).12, 11, 12, 13 These measurements inevitably ignore changes that may be occurring in other regions of the brain, and they are observer dependent. Several studies have shown increased atrophy in established Alzheimer's disease but most measurements show some overlap between age-related atrophy and that due to Alzheimer's disease, especially in the early stages of the disease.

Measurement based on a single scan does not make full use of the structural detail available, since small changes tend to be masked by the large biological variability among normal individuals. Acquisition of serial scans overcomes some of the difficulties because an individual's previous scan becomes the reference point, and the rate of change in, for example, ventricular enlargement or medial temporal lobe atrophy can be calculated.14, 15, 16 However, even with longitudinal studies, detection of small, diffuse changes remains difficult with manual volumetric measurement that involves outlining of regions of interest because the results are critically dependent on reproducible identification of anatomical structures and on the decisions as to which areas to examine.

Automated image subtraction offers an attractive alternative, because all areas of the brain can be examined simultaneously. However, very accurate positional matching (registration) of the scan is needed to compensate for different positioning of the patient within the scanner. Accurate registration to subvoxel level is possible with algorithms for automatic image registration.17, 18, 19 We have developed a procedure that produces accurate registration of scans while controlling for variations in image acquisition, such as voxel size and intensity.20, 21 This technique allows even small areas of atrophy to be seen by subtraction of the later from the earlier scan and display of those areas that have changed. Such atrophy can also be quantified to give regional or global measures of disease progression that should be more objective and robust than traditional volumetric studies. We report the results with this technique in patients with clinically diagnosed Alzheimer's disease, ranging in severity from presymptomatic to moderately affected.

Section snippets

Methods

Eleven patients (six male, five female) who met agreed criteria22 for the diagnosis of probable Alzheimer's disease were recruited from patients who were attending a specialist dementia clinic or were taking part in our longitudinal study of familial Alzheimer's disease. Three patients met the criteria for sporadic probable Alzheimer's disease and eight were affected members of early-onset familial Alzheimer's disease pedigrees. The diagnosis of the disorder in these familial cases is more

Results

The Alzheimer's disease patients and the controls did not differ significantly in age or scan interval (table). The controls all scored more than 28 out of 30 on the MMSE. The range of disease severity in the Alzheimer's disease patients was reflected in the range of MMSE scores at the time of their first scan (range 8–28). The three at-risk individuals scored 25, 28, and 30 on the MMSE at their initial scan and 24, 27, and 30 at their second scan. By the time of the second scan two individuals

Discussion

Accurate registration of serial MR brain scans permits the assessment of small amounts of diffuse structural change within the brain. This method is ideally suited to the unbiased detection and measurement of atrophy in Alzheimer's disease and other degenerative dementias. The distribution of atrophy can be seen and rates of atrophy, either global or regional, can be calculated. We have shown that accurate registration is possible with scans acquired under normal clinical conditions and with

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