Donepezil Treatment In Patients Research Articles

Investigation of the gait parameters after donepezil treatment in patients with alzheimer’ s disease

Introduction Clinical studies remark that gait disturbance is common in patients with Alzheimer’s disease (AD). However, the treatment response of gait disturbance in those patients may constitute a more interesting issue that is rarely addressed. Methods In this prospective, interventional study, we included 14 consecutive patients with a new diagnosis of AD. Basal gait analysis was performed using a ‘Gait Analyzer’ program that was uploaded to a mobile phone. The gait parameters including Step time (ST), step length (SL), step number (SN), gait velocity (GV), and cadence were measured. Afterward, donepezil 5 mg daily was initiated, and the re-assessments were re-performed 8 weeks after the treatment. Results The mean age was 71.78 ± 5.02 (F/M = 8/6). The evaluations after the donepezil treatment showed that there was a significant improvement in the SN (p = 0.021) and SL (p = 0.001) in comparison to the basal evaluations. The repeated analysis in the subgroup of early-stage AD subjects (n = 10) yielded that there were significant improvements in SN (p = 0.003), SL (p = 0.005), and cadence (p = 0.026) after treatment. Conclusions Our results support the efficiency of cholinergic treatment in gait functions in AD subjects.

Increased Hippocampal-Inferior Temporal Gyrus White Matter Connectivity following Donepezil Treatment in Patients with Early Alzheimer's Disease: A Diffusion Tensor Probabilistic Tractography Study.

The incidence of Alzheimer's disease (AD) has been increasing each year, and a defective hippocampus has been primarily associated with an early stage of AD. However, the effect of donepezil treatment on hippocampus-related networks is unknown. Thus, in the current study, we evaluated the hippocampal white matter (WM) connectivity in patients with early-stage AD before and after donepezil treatment using probabilistic tractography, and we further determined the WM integrity and changes in brain volume. Ten patients with early-stage AD (mean age = 72.4 ± 7.9 years; seven females and three males) and nine healthy controls (HC; mean age = 70.7 ± 3.5 years; six females and three males) underwent a magnetic resonance (MR) examination. After performing the first MR examination, the patients received donepezil treatment for 6 months. The brain volumes and diffusion tensor imaging scalars of 11 regions of interest (the superior/middle/inferior frontal gyrus, the superior/middle/inferior temporal gyrus, the amygdala, the caudate nucleus, the hippocampus, the putamen, and the thalamus) were measured using MR imaging and DTI, respectively. Seed-based structural connectivity analyses were focused on the hippocampus. The patients with early AD had a lower hippocampal volume and WM connectivity with the superior frontal gyrus and higher mean diffusivity (MD) and radial diffusivity (RD) in the amygdala than HC (p < 0.05, Bonferroni-corrected). However, brain areas with a higher (or lower) brain volume and WM connectivity were not observed in the HC compared with the patients with early AD. After six months of donepezil treatment, the patients with early AD showed increased hippocampal-inferior temporal gyrus (ITG) WM connectivity (p < 0.05, Bonferroni-corrected).

The measured CSF/plasma donepezil concentration ratio but not individually measured CSF and plasma concentrations significantly increase over 24 h after donepezil treatment in patients with Alzheimer’s disease

BackgroundThe acetylcholinesterase inhibitor donepezil is administered as a treatment for Alzheimer's disease (AD). However, the appropriate donepezil dosage is still a matter of debate. Methods: Forty AD patients receiving 10 mg/day of donepezil were randomly divided into four groups based on the time of plasma and cerebrospinal fluid (CSF) sampling: 6 h (n = 5), 12 h (n = 12), 18 h (n = 6) and 24 h (n = 17) after donepezil administration. High-performance liquid chromatography measured the donepezil concentration in plasma samples and CSF samples collected at 4-time points. Results: Plasma and CSF levels among the groups were not significantly different. Conversely, the CSF/plasma donepezil concentration ratio considerably increased in the 24 h group compared to the 6 h (p < 0.005) and 12 h (p < 0.05) groups. Conclusion: The measurement of the CSF/plasma donepezil concentration ratio could be used to better evaluate the optimal dose of donepezil.

White Matter Connectivity and Gray Matter Volume Changes Following Donepezil Treatment in Patients With Mild Cognitive Impairment: A Preliminary Study Using Probabilistic Tractography.

The donepezil treatment is associated with improved cognitive performance in patients with mild cognitive impairment (MCI), and its clinical effectiveness is well-known. However, the impact of the donepezil treatment on the enhanced white matter connectivity in MCI is still unclear. The purpose of this study was to evaluate the thalamo-cortical white matter (WM) connectivity and cortical thickness and gray matter (GM) volume changes in the cortical regions following donepezil treatment in patients with MCI using probabilistic tractography and voxel-based morphometry. Patients with MCI underwent magnetic resonance examinations before and after 6-month donepezil treatment. Compared with healthy controls, patients with MCI showed decreased WM connectivity of the thalamo-lateral prefrontal cortex, as well as reduced thickness in the medial/lateral orbitofrontal cortices (p < 0.05). The thalamo-lateral temporal cortex connectivity in patients with MCI was negatively correlated with Alzheimer's disease assessment scale-cognitive subscale (ADAS-cog) (r = −0.76, p = 0.01). The average score of the Korean version of the mini-mental state examination (K-MMSE) in patients with MCI was improved by 7.9% after 6-months of donepezil treatment. However, the patterns of WM connectivity and brain volume change in untreated and treated patients were not significantly different from each other, resulting from multiple comparison corrections. These findings will be valuable in understanding the neurophysiopathological mechanism on MCI as a prodromal phase of Alzheimer's disease in connection with brain functional connectivity and morphometric change.

Influence of CYP2D6, CYP3A5, ABCB1, APOE polymorphisms and nongenetic factors on donepezil treatment in patients with Alzheimer's disease and vascular dementia.

PurposeThis study aims to evaluate the influence of genetic polymorphisms of CYP2D6, CYP3A5, ABCB1, and APOE genes and nongenetic factors on steady-state plasma concentrations (Cpss) of donepezil and therapeutic outcomes in Thai patients with Alzheimer’s disease (AD) and vascular dementia (VAD).Patients and methodsEighty-five dementia patients who received donepezil for at least six months were recruited. CYP2D6, CYP3A5, ABCB1, and APOE polymorphisms were genotyped. Cpss of donepezil was measured. Association of genetic and non-genetic factors with Cpss and clinical outcomes of donepezil (cognitive function as measured by the Thai Mental State Examination score; TMSE) were determined by using univariate and multivariate analysis.ResultsBoth univariate and multiple linear regression analysis indicated that only CYP2D6*10 allele was associated with higher Cpss (p-value =0.029 and B =0.478, p-value =0.032, respectively) that might influence the clinical outcomes of donepezil. ie, TMSE (p-value =0.010 and B =4.527, p-value =0.001) and ΔTMSE (p-value =0.023 and B =4.107, p-value =0.002), especially in patients with AD. Interestingly, concomitant use of memantine was found to be associated with increased Cpss of donepezil (p-value =0.007 and B =0.511, p-value =0.014). Whereas, co-medication with antidepressant drugs attenuated clinical responses in patients with AD (TMSE: B =−2.719, p-value =0.013 and ΔTMSE: B =−2.348, p-value =0.028). Age was a significant predictor of donepezil response in VAD patients. No significant association of CYP3A5*3, ABCB1 3435C>T or ABCB1 1236C>T, and APOE ε4 genotypes with Cpss or clinical outcomes of donepezil was found in this study.ConclusionOur results suggests that CYP2D6*10 strongly influences Cpss and there is a trend toward better outcomes of donepezil in patients with AD. Nongenetic factors including concomitant drugs treatment might alter Cpss of donepezil or clinical outcomes.

Donepezil Treatment in Patients With Depression and Cognitive Impairment on Stable Antidepressant Treatment: A Randomized Controlled Trial

Depression and cognitive impairment are often comorbid in older adults, but optimal treatment strategies remain unclear. In a two-site study, the efficacy and safety of add-on donepezil versus placebo were compared in depressed patients with cognitive impairment receiving stable antidepressant treatment. A randomized, double-blind, placebo-controlled trial was conducted in older adults with depression and cognitive impairment (https://clinicaltrials.gov/ct2/show/NCT01658228; NCT01658228). Patients received open-label antidepressant treatment for 16 weeks, initially with citalopram and then with venlafaxine, if needed, followed by random assignment to add-on donepezil 5-10 mg daily or placebo for another 62 weeks. Outcome measures were neuropsychological test performance (Alzheimer's Disease Assessment Scale-Cognitive subscale [ADAS-Cog] and Selective Reminding Test [SRT] total immediate recall) and instrumental activities of daily living (Functional Activities Questionnaire). Of 81 patients who signed informed consent, 79 patients completed the baseline evaluation. Open antidepressant treatment was associated with improvement in depression in 63.93% responders by week 16. In the randomized trial, there were no treatment group differences between donepezil and placebo on dementia conversion rates, ADAS-Cog, SRT total immediate recall, or FAQ. Neither baseline cognitive impairment severity nor apolipoprotein E e4 genotype influenced donepezil efficacy. Donepezil was associated with more adverse effects than placebo. The results do not support adjunctive off-label cholinesterase inhibitor treatment in patients with depression and cognitive impairment. The findings highlight the need to prioritize discovery of novel treatments for this highly prevalent population with comorbid illnesses.

Higher levels of thyroxine may predict a favorable response to donepezil treatment in patients with Alzheimer disease: a prospective, case\u2013control study

BackgroundCholinergic hypothesis has been advanced as an etiology of Alzheimer disease (AD) on the basis of the presynaptic deficit found in the diseased brains, and cholinesterase inhibitors (ChEIs) are the treatment of choice for these patients. However, only about half of treatment efficacy was found. Because increasing evidence supports an extensive interrelationship between thyroid hormones (THs), cortisol level and the cholinergic system, the aim of the present study was to evaluate thyroid function and cortisol level in patients with mild to moderate AD before and after ChEIs treatment, and to identify possible variations in response. This was a prospective, case–control, follow-up study. Levels of cortisol and THs were evaluated in 21 outpatients with mild to moderate AD and 20 normal controls. All patients were treated with 5 mg/day of donepezil (DPZ) and were reevaluated after 24–26 weeks of treatment.ResultsThe patients had worse cognitive function, higher cortisol level, and lower levels of triiodothyronine (T3) and its free fraction than the controls. There were no significant differences in global cognitive function or cortisol level after treatment, however, significant reductions in T3 and thyroxin (T4) levels were observed. Responders had higher levels of T4 than non-responders, followed by a significant reduction after treatment.ConclusionsThese results suggest that relatively higher levels of T4 may predict a favorable response to DPZ treatment. Further studies are warranted to confirm the relationship between THs and ChEIs therapy in AD and to explore new therapeutic strategies. On the other hand, cortisol levels are more likely to respond to interventions for stress-related neuropsychiatric symptoms in patients with AD rather than ChEIs treatment. Further studies are warranted to investigate the association between cortisol level and the severity of stress-related neuropsychiatric symptoms in patients with AD.

Effect of the CYP2D6 and APOE Polymorphisms on the Efficacy of Donepezil in Patients with Alzheimer's Disease: A Systematic Review and Meta-Analysis.

Differential responses to donepezil treatment in patients with Alzheimer's disease (AD) have been observed in clinical practice. It remains controversial whether, and to what extent, individual variation in the genes responsible for drug metabolism (CYP2D6) or those associated with AD pathogenesis (APOE) modulate the response to donepezil treatment. The aim of this study was to better understand the potential link betweendonepezil treatment response and CYP2D6 or APOE polymorphisms. We performed a meta-analysis based on data collected from 1266 donepezil-treated AD patients, and evaluated the association of CYP2D6 or APOE polymorphisms with treatment effectiveness. No significant difference was observed in the responder rate of donepezil treatment between the normal function CYP2D6 alleles group and the decreased/non-functional group [odds ratio (OR) 1.34, 95% confidence interval (CI) 0.5-3.58; p=0.56]. However, compared with the increased function CYP2D6 alleles group, the normal function group had a better response to donepezil treatment (OR 1.52, 95% CI 1.14-2.03; p=0.005). For the specific CYP2D6 single nucleotide polymorphism rs1080985, patients who carried the G allele had a significantly higher risk of poor response to donepezil treatment. After adjusting the data based on APOE genotype, it was observed that only individuals bearing both the APOE-ε4 allele and the rs1080985-G allele showed a significant increase in the frequency of treatment non-response (OR 1.73, 95% CI 1.07-2.09; p=0.03). No independent effect of APOE polymorphism on donepezil clinical responses was found (OR 1.08, 95% CI 0.85-1.38; p=0.53). Lastly, in a subgroup analysis based on ethnicity, all results remained consistent. The CYP2D6 genotype may be potentially effective for predicting the response to donepezil treatment in AD patients.

Effects of donepezil on brain morphometric and metabolic changes in patients with Alzheimer's disease: A DARTEL-based VBM and 1H-MRS

A few studies have performed on the brain morphometric changes over the whole brain structure following donepezil treatment in patients with Alzheimer's disease (AD). We evaluated the gray matter (GM) and white matter (WM) volume alterations and cellular metabolic changes in patients with AD before and after donepezil treatment, and further to reveal the correlations of the scores of various neuropsychological scales with the volumetric and metabolic changes. Twenty-one subjects comprising of 11 patients with AD and 10 age-matched healthy controls participated in this study. All of the patients participated in the follow-up study 24weeks following donepezil treatment. In this study, a combination of voxel-based morphometry (VBM) and proton magnetic resonance spectroscopy (1H-MRS) was used to assess the brain morphometric and metabolic alterations in AD. In the GM volumetric analysis, both of the untreated and treated patients with donepezil showed significantly reduced volumes in the hippocampus (Hip), parahippocampal gyrus (PHG), precuneus (PCu) and middle frontal gyrus compared with healthy controls. However, donepezil-treated patients showed significantly increased volumes in the Hip, PCu, fusiform gyrus and caudate nucleus compared to untreated patients. In the WM volumetric analysis, untreated and treated patients showed significant volume reductions in the posterior limb of internal capsule (PLIC), cerebral peduncle of the midbrain and PHG compared to healthy controls. However, there was no significant WM morphological change after donepezil treatment in patients with AD. In MRS study, untreated patients with AD showed decreased N-acetylaspartate/creatine (NAA/Cr) and increased myo-inositol (mI)/Cr compared to healthy controls, while treated patients showed only decreased NAA/Cr in the same comparison. However, the treated patients showed simultaneously increased NAA/Cr and decreased mI/Cr and choline (Cho)/Cr ratios compared to untreated patients. This study shows the regional GM and WM volume changes in combination with metabolic changes following donepezil treatment in AD. These findings would be helpful to aid our understanding of the neuroanatomical mechanisms associated with effects of donepezil on the cognitive function in AD.

Influence of the rs1080985 Single Nucleotide Polymorphism of the CYP2D6 Gene and APOE Polymorphism on the Response to Donepezil Treatment in Patients with Alzheimer's Disease in China

Background/Aim: Recent data have indicated that the rs1080985 single nucleotide polymorphism (SNP) of the cytochrome P450 (CYP) 2D6 and the common apolipoprotein E (APOE) gene may affect the response to donepezil in patients with Alzheimer's disease (AD). We investigated this association in Chinese patients with mild-to-moderate AD. Methods: In this prospective cohort study, analyses of CYP2D6 and APOE were conducted in 208 native Chinese patients with mild-to-moderate AD. All patients were treated with donepezil 5 mg/day for 6 months, and the response to treatment was assessed using the Mini-Mental State Examination. Results: No significant differences between responders (68.9%) and nonresponders (31.1%) to donepezil treatment (6 months' duration) were observed in the distribution of the CYP2D6 rs1080985 SNP, common APOE polymorphism or a combination of the two. Conclusions: Our results suggest that neither the CYP2D6 nor the APOE polymorphism influences the 6-month response to donepezil treatment in a Chinese population with AD.

Parallel Improvement of Cognitive Functions and P300 Latency Following Donepezil Treatment in Patients With Alzheimer's Disease

To evaluate the effect of donepezil, one of the cholinesterase inhibitors, on P300 measurements in patients with Alzheimer's disease (AD) and investigate the relationship between the subfactors of cognitive performance and P300 components. One hundred outpatients with AD were evaluated for cognitive function (cognitive ability screening instrument) and event-related potentials before and after 22 to 23 weeks of treatment with donepezil (5 mg/day). Twenty age-matched normal control subjects were recruited. The patients with AD showed prolonged P300 and N200 latency, no significant differences in N100 and P200 components, and poor performance in neuropsychological assessments compared with control subjects at baseline. After donepezil treatment, the patients with AD had reduction in P300 latency at Pz lead, which was associated with a parallel improvement in cognitive function in terms of remote memory, recent memory, visual instruction, and orientation. The pre-post treatment difference of P300 latency significantly correlated with the cognitive ability screening instrument score difference and recent memory score difference, respectively. The patients with AD still had intact early sensory processing but impaired higher-level cognitive processes that could influence behavior deviation. The donepezil treatment, which enhances higher-level cognitive processing time, revealed that P300 latency decreases as cognitive capability increases, especially improved in recent memory.

Effect of Donepezil on Sleep and Activity in Alzheimer’s Disease: Actigraphic and Polysomnographic Assessment

Aim: To examine the effect of donepezil on sleep and daily activity in patients with Alzheimer-type dementia (ATD) using polysomnography and actigraphy. Methods: Ten patients with mild to moderate ATD (mean age: 76 ± 6.2 years) were studied. The Alzheimer’s disease Assessment Scale-cognitive component-Japanese version (ADAS-Jcog),polysomnography, and 7-day recording of actigraphy data were performed. Following this baseline assessment, donepezil (5 mg daily) was administered every morning for 6 weeks, after which the ADAS-Jcog, polysomnography, and actigraphy were repeated. Results: After 6 weeks of treatment with donepezil, daily activity was significantly increased (276.2 ± 89.2 vs. 326.1 ± 98.6; p < 0.05). Similarly, rapid eye movement (REM) sleep (11.3 ± 4.1 vs. 17.1 ± 4.4; p<0.01) and sleep efficiency (76.2 ± 16.3 vs. 82.8 ± 10.6; p<0.05) were significantly increased compared with baseline. Although the ADAS-Jcog score did not decrease significantly (18.5 ± 6.8 vs. 15.9 ± 7.3; P= 0.054), there was a significant positive correlation between the decrease of this score and the increase of daily activity (r= 0.2137, p= 0.4809). Conclusions: An increase of daily activity and cognition were induced by donepezil treatment in patients with ATD, possibly based on improvement of the sleep structure. Trial Registration: Controlled-trials. Com Identifier: UMIN000005018

The influence and changes in the dosages of concomitantly used psychotropic drugs associated with the discontinuation of donepezil in severe Alzheimer’s disease with behavioral and psychological symptoms on dementia: a preliminary open-label trial

We investigated the influence on behavioral and psychological symptoms on dementia (BPSD) and the changes in the dosages of concomitant psychotropic drugs associated with the discontinuation of donepezil in patients with severe Alzheimer's disease (AD) who developed BPSD during donepezil therapy. The subjects were 44 inpatients who had been diagnosed with AD according to the Diagnostic and Statistical Manual of Mental Disorders IV (DSM-IV). The outcome measures assessed were BPSD and cognitive function. BPSD was assessed using the Neuropsychiatric Inventory (NPI) and cognitive function was assessed using the Mini Mental Examination (MMSE). The changes in the dosages of concomitant psychotropic drugs were also assessed. Significant decreases were found in the donepezil treatment discontinuation group in the following NPI total score and two NPI subscales (agitation and irritability), but no significant differences were seen between the donepezil treatment discontinuation group and the control group. Furthermore, the mean changes from baseline in the risperidone equivalent dose and the diazepam equivalent dose were hardly changed in the donepezil treatment discontinuation group. The results of this study suggest that the discontinuation of donepezil treatment in patients with AD with BPSD may afford superior efficacy and may make it possible to not increase the dosage of other psychotropic drugs.

Efficacy of memantine in people with moderate to severe Alzheimer's disease with and without background donepezil therapy: Pooled analysis of four randomized trials

Memantine is an NMDA receptor antagonist approved for the treatment of moderate to severe Alzheimer's disease (AD); donepezil is a cholinesterase inhibitor (ChEI), approved for mild to severe AD in the US. Treatment of AD typically involves initiation of donepezil therapy in early stages, with memantine added as the disease progresses to moderate and severe stages. Two large 24-week randomized trials and several observational studies suggest that this combined treatment is superior to monotherapy with either drug; while results of one small 52-week randomized trial generated debate. To further investigate the effects of combination therapy vs monotherapy, we pooled four similarly designed randomized, placebo-controlled trials of memantine in patients with moderate to severe AD and compared Baseline-to-Endpoint changes in measures of cognition (SIB), function (ADCS-ADL 19), behavior (NPI), and global clinical status (CIBIC-Plus), stratified by treatment/concurrent therapy regimen (placebo, memantine, placebo/donepezil, or memantine/donepezil). All patients from two memantine monotherapy trials (MRZ-9001–9605 and MEM-MD-01; N=567) and donepezil-treated patients from two memantine add-on trials (MEM-MD-02 and MEM-MD-50; N=841) were pooled and Endpoint changes from Baseline for the SIB, ADCS-ADL 19, NPI, and CIBIC-Plus were assessed using a mixed-effects model with repeated measures (observed cases). Due to the exploratory nature of this analysis, no corrections for multiple comparisons were performed. At study Endpoint, the memantine/donepezil treatment group was significantly superior to placebo (P<0.001) and both memantine and placebo/donepezil monotherapy groups (P<0.05) on all four efficacy measures. There were no statistically significant differences between memantine and placebo/donepezil monotherapy groups on the CIBIC-plus, ADCS-ADL 19, and NPI; however, the placebo/donepezil group performed significantly better than the memantine group on the SIB (P<0.001). Both memantine and placebo/donepezil treatment groups were significantly better than placebo on the SIB, ADCS-ADL 19, and CIBIC-plus (P<0.01), but no significant treatment differences were observed among these three treatment groups on the NPI. This pooled analysis is in agreement with evidence suggesting that adding memantine to stable donepezil treatment in patients with moderate to severe AD is associated with improvements across several clinical domains, compared with monotherapy using either drug. Appropriately powered, long-term, prospective studies of add-on therapy in AD are warranted.

A clinical phase II study of Lu AE58054 added to stable donepezil treatment in patients with moderate Alzheimer's disease

A clinical phase II study of Lu AE58054 added to stable donepezil treatment in patients with moderate Alzheimer's disease

Role of cytochrome P4502D6 functional polymorphisms in the efficacy of donepezil in patients with Alzheimer's disease

Cytochrome P450 (CYP) 2D6 enzyme is the major responsible for the metabolism of donepezil, an inhibitor of acetyl cholinesterase currently used for the symptomatic treatment of mild-to-moderate Alzheimer's disease (AD). Functional polymorphisms in the CYP2D6 gene may affect enzyme activity and thus, the metabolism of donepezil. The aim of this study was to evaluate the effect of 16 functional polymorphisms in the CYP2D6 gene on the clinical response to donepezil treatment in patients with mild-to-moderate AD. In this multicenter prospective cohort study we evaluated 57 unrelated Caucasians clinically diagnosed as AD according to the National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer's Disease and Related Disorders Association Work Group criteria. Patients were treated with donepezil (5-10 mg/daily) for 6 months. The response to donepezil treatment was evaluated at 6-month follow-up according to the National Institute for Health and Clinical Excellence requirements. The identification of 16 clinically relevant CYP2D6 gene variants was performed by a high-throughput genetic analysis. Thirty-eight of 57 patients (67%) were responders and 19 patients (33%) were nonresponders to donepezil treatment. A significantly higher frequency of gene variants conferring decreased or absent enzyme activity was observed in responder than in nonresponder patients (73.68% vs. 36.84%; P=0.005). The presence of gene variants conferring decreased or absent activity of the CYP2D6 enzyme was significantly associated with a clinical response to donepezil treatment (odds ratio=6.286; 95% confidence interval=1.828-21.667). Functional polymorphisms in the CYP2D6 gene can influence the clinical efficacy of donepezil. The analysis of CYP2D6 genotypes may be useful in identifying subgroups of AD patients with different clinical response to donepezil treatment.

Effects of donepezil on amyloid-β and synapse density in the Tg2576 mouse model of Alzheimer's disease

Donepezil, an acetylcholinesterase inhibitor, is an approved drug for the treatment of Alzheimer's disease (AD). Although extensive studies have demonstrated the symptomatic efficacy of donepezil treatment in patients with AD, the effects of donepezil, if any, on the AD process are not known. In this study, we sought to determine whether long-term administration of donepezil would slow amyloid plaque deposition or confer neuronal protection in a mouse model of AD. We used quantitative light and electron microscopy to investigate the effects of long-term administration (from 3 to 9 months of age for 6 months of treatment) of donepezil (1, 2, 4 mg/kg, in drinking water) on tissue amyloid-β (Aβ) protein, plaque deposition, synaptic protein (synaptophysin), and synapse density in the hippocampus of Tg2576 mice. Administration of the 4 mg/kg dose of donepezil, as compared to vehicle and lower doses of donepezil, significantly reduced brain tissue soluble Aβ1–40 and Aβ1–42, Aβ plaque number, and burden at the study end point in Tg2576 mice. The dose of 4 mg/kg of donepezil also significantly increased synaptic density in the molecular layer of the dentate gyrus in Tg2576 mice. However, a significant change of the synaptophysin-positive bouton in the hippocampus was not observed. These results suggest that a higher dose of donepezil may have a measurable impact on tissue level of Aβ protein and plaque deposition and may prevent synapse loss in the Tg2576 mouse model of AD.

Increase of SCF plasma concentration during donepezil treatment of patients with early Alzheimer's disease

Alzheimer's disease (AD) can be treated with inhibitors of the enzyme acetylcholinesterase (AChE). There is evidence that AChE inhibitors promote neuroprotective effects and neurogenesis in the central nervous system (CNS). However, the mechanisms by which AChE inhibitors mediate these effects are still not well understood. One possible mechanism could be the up-regulation of haematopoietic growth factors (HGFs), also known to promote neuroprotective effects and to stimulate neurogenesis in the CNS. In the present study we investigated the impact of a 15-month treatment with the AChE inhibitor donepezil on blood levels of the HGFs stem cell factor (SCF), stromal cell-derived factor 1 (SDF-1), granulocyte colony- stimulating factor (G-CSF) and vascular endothelial growth factor (VEGF) in 19 patients with AD and 45 age-matched healthy controls. Before treatment with donepezil we found in AD patients significantly decreased SCF plasma concentrations (661.1+/-40.0 pg/ml) compared to healthy controls (997.7+/-33.7 pg/ml, p<0.001) but no significant differences between both groups concerning blood levels of SDF-1, G-CSF and VEGF. After 15 months' treatment SCF plasma levels increased significantly in the AD patients (764.5+/-41.5 pg/ml, p=0.016). In addition, we found a significant positive correlation between SCF plasma levels at baseline and changes of cognitive functions over the 15-month period (r=0.521, p=0.022). For the other HGFs we were unable to show a significant impact of donepezil treatment. Our findings indicate that donepezil treatment of AD patients is associated with an up-regulation of SCF plasma levels, which may contribute to neuroprotection and neurogenesis in the CNS.

Donepezil treatment of patients with MCI

Treatment of mild cognitive impairment (MCI) with cholinesterase inhibitors may improve symptoms. In this multicenter, randomized, placebo-controlled trial, subjects with MCI entered a 3-week placebo run-in period followed by 48 weeks of double-blind donepezil (5 mg/day for 6 weeks, then 10 mg/day for 42 weeks) or placebo treatment. Primary efficacy variables included change from baseline in the modified Alzheimer Disease Assessment Scale-cognitive subscale (ADAS-Cog) and Clinical Dementia Rating Scale-sum of boxes (CDR-SB) after 48 weeks of treatment (modified intention-to-treat analysis). Secondary efficacy measures evaluated cognition, behavior, and function. The dual primary efficacy endpoint was not reached. We noted a small, but significant, decrease in modified ADAS-Cog scores in favor of donepezil at study endpoint. Little change from baseline in CDR-SB and secondary variables was observed for either group. Patient Global Assessment scores favored donepezil at all time points except week 12 (p < or = 0.05). Perceived Deficits Questionnaire scores favored donepezil at week 24 (p = 0.05). Clinical Global Impression of Change-MCI scores favored donepezil only at week 6 (p = 0.04). Adverse events were generally mild or moderate. More donepezil-treated subjects (18.4%) discontinued treatment due to adverse events than placebo-treated subjects (8.3%). Donepezil demonstrated small but significant improvement on the primary measure of cognition but there was no change on the primary measure of global function. Most other measures of global impairment, cognition, and function were not improved, possibly because these measures are insensitive to change in MCI. Responses on subjective measures suggest subjects perceived benefits with donepezil treatment.

SPECT-Identified Neuroanatomical Predictor of the Cognitive Effects of Donepezil Treatment in Patients with Alzheimer’s Disease

Background/Objective: We attempted to determine whether the pretreatment regional cerebral blood flow (rCBF) might predict cognitive changes in response to donepezil treatment, as assessed in terms of the Alzheimer Disease Assessment Scale cognitive subscale (ADAS-cog), and in relation to the severity of subcortical hyperintensities (SH). Method: Forty-one patients with Alzheimer’s disease (AD) were treated with donepezil at baseline. All the patients underwent a single photon emission computed tomography examination before donepezil therapy. They also completed the ADAS-cog at baseline and after 24 weeks of donepezil therapy. SH were assessed semiquantitatively using a recently developed visual rating scale. We analyzed the correlation between the baseline rCBF and changes in the ADAS-cog score using statistical parametric mapping, including the severity of the SH as a covariate. Results: Lower pretreatment rCBF levels in the right orbitofrontal cortex (OFC) predicted a better improvement in the ADAS-cog score in response to donepezil therapy. The severity of SH did not appear to influence this correlation. Conclusions: This effect may reflect the choline acetyltransferase activity associated with the OFC. The presence of SH did not appear to influence the effect of donepezil therapy on the cognitive function as assessed by ADAS-cog.