GOOD or BAD Responder? Behavioural and Neuroanatomical Markers of Clinical Response to Donepezil in Dementia

Abstract

Abstract. We explored the neuropsychological and neuromorphometrical differences between probable Alzheimer's disease patients showing a good or a bad response to nine months treatment with donepezil. Before treatment, the neuropsychological profile of the two patient groups was perfectly matched. By the ninth month after treatment, the BAD-responders showed a decline of the MMSE score together with a progressive impairment of executive functions. A voxel-based morphometry investigation (VBM), at the time of the second neuropsychological assessment, showed that the BAD-responders had larger grey and white matter atrophies involving the substantia innominata of Meynert bilaterally, the ventral part of caudate nuclei and the left uncinate fasciculus, brain areas belonging to the cholinergic pathways. A more widespread degeneration of the central cholinergic pathways may explain the lack of donepezil efficacy in those patients not responding to a treatment that operates on the grounds that some degree of endogeneous release of acetylcholine is still available.

Basal Forebrain Volume, but Not Hippocampal Volume, Is a Predictor of Global Cognitive Decline in Patients With Alzheimer's Disease Treated With Cholinesterase Inhibitors

“…Our findings indicate that in the presence of cholinergic treatment, a high cholinergic basal forebrain volume is associated with more benign global cognitive decline. Our findings agree with a previous exploratory study, where response to cholinergic treatment over 9 months as measured by the MMSE score was significantly associated with gray matter volume in basal forebrain regions from a voxel based regression analysis in 23 AD cases ( 54 ). Our findings disagree with a study in 82 AD dementia patients using the substantia innominata thickness as a proxy of cholinergic basal forebrain integrity ( 18 ); here smaller rate of cognitive decline was found associated with a smaller thickness of the substantia innominata during 9 months cholinergic treatment ( 19 ).…”

Comparison of neuropsychological and functional outcomes in Alzheimer's disease patients with good or bad response to a cognitive stimulation treatment: a retrospective analysis

“…According to our results, 51.7% of patients were classified as responders, based on present stability or improvement of global cognitive function after 12 months of treatment. Importantly, we opted for a conservative approach as the primary measure of treatment outcome of CS (no change or improvement on the annual rate of change using MMSE) and following the criteria of other previous studies (Bottini et al, 2012;Woods et al, 2012;Binetti et al, 2013). This finding concurs with those of a previous study on predictors of efficacy to CS programs (Binetti et al, 2013) and other studies on factors associated with response to predictors of responsiveness to treatment with Table 4.…”

“…The annual rate of change scores on the MMSE was calculated by subtracting T0 MMSE score from T1 score. This allowed us to distinguish responders (R) to CS from non-responders (NR), following the criteria of other previous studies (Bottini et al, 2012;Woods et al, 2012;Binetti et al, 2013). No change or improvement on the annual rate of change (score ≥0 was considered a positive sign of response to treatment, and subjects were classified as R.…”

Malignant Synaptic Growth and Alzheimer‘s Disease

“…Many treatments for Alzheimer’s disease have focused on restoring basal cholinergic levels through blockade of central acetylcholinesterase [1,2], but these have been met with only moderate success. The malignant synaptic growth hypothesis provides a unique perspective on why cholinergic treatments may yield modest or inconsistent results.…”

“…Current treatments for Alzheimer’s disease offer only a small reduction in behavioral symptoms [1,2] and do not halt the temporal progression of the disease – emphasizing the need for a functional framework for understanding the progression of the disease. The primary existing hypotheses of the root cause of Alzheimer’s disease typically focus on specific molecular pathways and do not address the characteristic anatomical progression of tangle pathology [3].…”