Early And Widespread Cholinergic Losses Differentiate Dementia With Lewi Bodies From Alzheimer’s Disease
Tiraboschi P, Hansen LA, Alford M, Merdes A, Mashah E, Thal LJ and Corey-Bloom J;
Commented by , 22 Nov 2002
Aim of the Study
To compare Choline Acetyl Transferase (ChAT) activity in Alzheimer’s Disease (AD) and Lewi Body Dementia (LBD), at different stages of severity of dementia.
Method
Patients were drawn from those assessed longitudinally at the San Diego Alzheimer’s Disease Research Centre. Inclusion criteria were:
1) All normal controls or patients with a clinical diagnosis of AD or LBD, (using standard diagnostic criteria), who underwent autopsy from 1985 – 2002. Autopsy was performed within 12 hours of death using a standardised protocol.
2) ChAT activity available, using standardised neurochemical tests.
3) Cognitive testing had been administered within the period 2 years prior to death. The main test used was the Folstein Mini Mental State Examination (MMSE).
Statistical analysis was performed for mean ChAT activity for AD vs normal controls, and LBD vs normal controls, using 1-way analysis of variance (ANOVA). When a statistically significant result was obtained, correlation analysis was performed for AD vs LBD patients.
Results
As expected, disease duration increased and cognitive performance decreased with disease stage, and ChAT activity was significantly decreased in both AD and LBD cohorts.
However, loss of ChAT was much greater for LBD patients, despite comparable mean ages at death, death-test intervals and disease severity. Specifically, decline in ChAT activity was only statistically significant in late stage AD, whereas decline in ChAT activity was significant at earlier stages of LBD (MMSE > or = 20).
Moreover, ChAT activity was reduced in all brain areas in early stage LBD, but was more region-specific in AD – for example, inferior parietal and midfrontal cortex were only affected in late stage AD.
There were similar findings for ChAT activity using correlation analysis between AD and LBD cohorts for the last MMSE score before death – ChAT activity was overall less for LBD patients.
Discussion
Loss of ChAT activity has been shown to correlate with cognitive decline in AD by several investigators, though the correlation is less clear in LBD. ChAT activity is the best neurochemical marker to assess cognitive decline.
This is the first large-scale autopsy study to look at ChAT activity at different stages of LBD. As the authors acknowledge, it is a cross-sectional study on a selected population, so definite conclusions about longitudinal changes in individual patients cannot be drawn. However, the differences between AD and LBD are striking.
The potential therapeutic implications are:
1) Patients with advanced AD have the potential to respond to cholinergic treatment, perhaps more so than in early stage disease, where treatment efforts with cholinesterase inhibitors are currently focussed. Should we be withdrawing cholinesterase inhibitors in AD when MMSE drops below 12, as guidelines suggest, at a time when patients theoretically may derive most benefit?
2) Cholinergic replacement therapy may be particular effective in LBD, beginning with the earliest stages (McKeith’s group in Newcastle have previously reported this).
3) This study provides theoretical support for the clinical observation that cholinesterase inhibitors are effective in treating neuropsychiatric symptoms of agitation, delusions and hallucinations that are particularly prominent in LBD, but also occur in AD.