Atrophy of the substantia innominata on Magnetic Resonance Imaging predicts response to donepezil treatment in Alzheimer’s disease patients.
Tanaka Y, Hanyu H, Sakurai H, Takasaki M and Abe K;
Commented by , 25 Sep 2003
Aim of the study
To investigate if atrophy of the substantia innominata (SI) as show on magnetic resonance imaging (MRI) shows an inverse correlation with clinical response to treatment with donepezil in patients with Alzheimer’s disease (AD).
Method
88 outpatients with probable AD, severity range of 12 to 24 on the Mini Mental State Examination (MMSE) and 1 or 2 on the Clinical Dementia Rating, had brain MRI followed by 12 months treatment with donepezil 5mg/day.
Clinical efficacy was measured using MMSE after 3 and 12 months of treatment. Patterns of clinical responses were pre-defined using MMSE score changes between baseline, 3 and 12 months, as
- “responders”: 4 points or more improvement at 3 months
- “continuous responders”: 4 points or more at 3 and 12 months
- “transient responders”: 4 points or more at 3 months, 3 points or less at 12 months
- “non responders”: 3 points or less at 3 months. Statistical analysis was performed using a one-way analysis of variance with a post hoc Scheffé F test, chi square test, Winconsin signed-rank test. Correlations between the thickness of the SI and MMSE score changes were calculated using Spearman’s rank correlation test
Results
82 patients were eligible since the SI could not be clearly measured in 6 subjects. Thirteen were “continuous responders”, 21 “transient responders”, 48 “non responders”.
No differences were found at baseline between groups at baseline in terms of age, gender, MMSE scores and education. Statistically significant differences for the thickness of SI was found between both groups of responders and non responders (p<0.01 and p<0.001 respectively).
Statistically significant inverse correlations were found between the thickness of SI and MMSE score changes at 3 months (r= -0.51, p<0.0001) and at 12 months (r= -0.36, p<0.01).
Logistic regression analysis showed that the discrimination rate was 70%, with 69% of non responders and 71% of responders, using a cutoff value of 1.81mm or less for the thickness of SI.
Discussion
The loss of cholinergic neurons in the SI along with depletion of choline acetyltransferase activity in the cortex is the basis of the cholinergic hypothesis of AD, leading to current symptomatic drugs such as donepezil, rivastigmine and galantamine.
There is no unanimity of why certain patients with AD improve more than others with these drugs, but it is clear that patients with Dementia with Lewy Bodies improve the most.
Such patients are known to have a worse depletion of cholinergic cell bodies than patients with AD. It was thus logical for the authors of this study to use a surrogate marker of cholinergic depletion, the thickness of SI using MRI, to validate the inverse correlation between cholinergic depletion and clinical response to a cholinesterase inhibitor.
It should be noted that whole brain volumetry using serial MRI is currently used as surrogate marker of disease progression in clinical trials aiming at disease modification.
The authors should be complimented for their definition of ‘responders’ based on a clinical tool used by all clinicians world-wide.
The lower doses of donepezil used in Japan, based on the pivotal study of Homma et al. (1) are indeed effective in half the patients over one year, if improvement of cognition above baseline is used as criteria. Non-cognitive features of AD have also been found to be important in determining the success of treatment over one year (2).
This study testifies to the seminal work done by clinical investigators in Japan, who will host the annual meeting of Alzheimer Disease International in Kyoto, October 2004.
References
1. Homma et al., Dementia and Geriatric Cognitive Disorders 2000; 11; 299-313
2. Winblad et al., International Journal of Geriatric Psychiatry 2001; 16; 653-666