Improvements In ADAS-Cog Research Articles

Effectiveness of Personalized Hippocampal Network–Targeted Stimulation in Alzheimer Disease

Repetitive transcranial magnetic stimulation (rTMS) has emerged as a safe and promising intervention for Alzheimer disease (AD). To investigate the effect of a 4-week personalized hippocampal network-targeted rTMS on cognitive and functional performance, as well as functional connectivity in AD. This randomized clinical trial, which was sham-controlled and masked to participants and evaluators, was conducted between May 2020 and April 2022 at a single Korean memory clinic. Eligible participants were between ages 55 and 90 years and had confirmed early AD with evidence of an amyloid biomarker. Participants who met the inclusion criteria were randomly assigned to receive hippocampal network-targeted rTMS or sham stimulation. Participants received 4-week rTMS treatment, with assessment conducted at weeks 4 and 8. Data were analyzed between April 2022 and January 2024. Each patient received 20 sessions of personalized rTMS targeting the left parietal area, functionally connected to the hippocampus, based on fMRI connectivity analysis over 4 weeks. The sham group underwent the same procedure, excluding actual magnetic stimulation. A personalized 3-dimensional printed frame to fix the TMS coil to the optimal target site was produced. The primary outcome was the change in the AD Assessment Scale-Cognitive Subscale test (ADAS-Cog) after 8 weeks from baseline. Secondary outcomes included changes in the Clinical Dementia Rating-Sum of Boxes (CDR-SOB) and Seoul-Instrumental Activity Daily Living (S-IADL) scales, as well as resting-state fMRI connectivity between the hippocampus and cortical areas. Among 30 participants (18 in the rTMS group; 12 in the sham group) who completed the 8-week trial, the mean (SD) age was 69.8 (9.1) years; 18 (60%) were female. As the primary outcome, the change in ADAS-Cog at the eighth week was significantly different between the rTMS and sham groups (coefficient [SE], -5.2 [1.6]; P = .002). The change in CDR-SOB (-4.5 [1.4]; P = .007) and S-IADL (1.7 [0.7]; P = .004) were significantly different between the groups favoring rTMS groups. The fMRI connectivity analysis revealed that rTMS increased the functional connectivity between the hippocampus and precuneus, with its changes associated with improvements in ADAS-Cog (r = -0.57; P = .005). This randomized clinical trial demonstrated the positive effects of rTMS on cognitive and functional performance, and the plastic changes in the hippocampal-cortical network. Our results support the consideration of rTMS as a potential treatment for AD. ClinicalTrials.gov Identifier: NCT04260724.

Effectiveness of cognitive stimulation therapy (CST) on cognition, quality of life and neuropsychiatric symptoms for patients living with dementia: A meta-analysis

IntroductionMany scholars have explored the effect of cognitive stimulation therapy (CST) on dementia patients, however, due to different experimental designs and insufficient sample sizes, research results are inconsistent. Furthermore, there is a scarcity of high-quality quantitative results. ObjectiveTo assess the effectiveness of CST for improving cognition, quality of life (QoL) and neuropsychiatric symptoms in people with dementia (PwD). MethodsChinese and English databases were searched for randomized controlled trials (RCTs) between establishment of and April 2022, with another search done in May 2022. Finally, 10 studies on the application of CST in PwD for improving cognition, QoL, behavior, language and activities of daily living were reviewed. ResultsBased on the results of the 10 RCTs, CST significantly improved cognitive performance (MMSE: WMD = 1.98, 95% CI: 1.24–2.72, P<0.01), QoL (WMD = 3.12, 95% CI: 2.52–3.72, P<0.01), language (NLT: WMD = 2.71, 95% CI: 1.07–4.35, P<0.01) and activities of daily living (DAD: WMD = 7.27, 95% CI: 0.97–13.56, P<0.01) in PwD. However, no significant improvements in ADAS-Cog (WMD = 0.55, 95% CI: -3.04–4.14, P = 0.76), depression (SMD = -0.12,95% CI: -0.29–0.04, P = 0.15), anxiety (RAID: WMD = -1.05, 95% CI: -3.85–1.75, P = 0.46) or neuropsychiatric symptoms (NPI: WMD = 0.23, 95% CI: -2.62–3.07, P = 0.88) were found. ConclusionCST improved the cognitive ability, QoL, language and activities of daily living of PwD. However, the effect of neuropsychiatric symptoms on PwD requires further exploration.

ENGAGEMENT MATTERS TO OPTIMIZE COGNITIVE BENEFITS OF COGNITIVELY IMPAIRED PEOPLE IN COGNITIVE STIMULATION THERAPY

Background Cognitive stimulation therapy (CST), a 14-session themed groupwork for people with cognitive impairment, shows effectiveness in maintaining cognitive functioning, quality of life and communication. However, its mechanism of optimizing individual cognitive benefits is little known. Engagement, a state of being occupied by meaningful external stimuli, may be an overlooked link. Individual constructive engagement is defined as the verbal or motor individual behavior exhibited for the meaningful purposed activities. Objective To investigate the individual experience of engagement in CST and its effect on cognitive benefits. Methods A total of 108 participants were recruited from 8 community centers, 2 daycare centers and 2 residential care units in Hong Kong. Trained assessors not involved in CST delivery conducted the pre-and-post assessments using Alzheimer’s Disease Assessment Scale-Cognitive Subscale (ADAS-Cog). Trained raters observed each participant’s engagement under six 5-minute observation windows in total during CST sessions by time sampling using the adapted Myers Institute Engagement Scale. Results Paired t-test shows significant improvement in ADAS-Cog (Pretest: M=22.71, SD=12.63; Posttest: M=19.06, SD=10.93; MD=3.65, SD=7.38, t=5.138, p<.000). Individual constructive engagement was exhibited 23.3% of activity time averagely. It correlated with the change in ADAS-Cog positively(r=.292, p<.002). Greater individual constructive engagement predicted lower post-intervention ADAS-Cog score (B=-14.98, β=-.192, p<.001), indicating a better cognitive functioning, after controlling baseline ADAS-Cog score (B=.707, β=.816, p<.000) in the multiple linear regression analysis (R2 = .698, F (2,105) =121.38, p<.000). Conclusion Engagement is the potential mechanism to maximize individual cognitive benefits. Future studies can investigate contributing factors of engagement to improve intervention effectiveness

Safety and efficacy of active and passive immunotherapy in mild-to-moderate Alzheimer's disease: A systematic review and network meta-analysis.

The objective of this study was to systematically review and conduct a direct and network meta-analysis of randomized controlled trials that have examined the clinical safety and efficacy of using passive and active immunotherapies in Alzheimer's disease (AD). (1) Is amyloid-based immunotherapy in patients with mild-to-moderate AD associated with more efficacy benefits compared to placebo? (2) Which immunotherapy agent is associated with more comparative benefit? (3) Is passive or active immunotherapy associated with more benefits? A systematic review of published randomized controlled trials was performed in MEDLINE, EMBASE, PubMed and Cochrane library. Review methods and meta-analysis: Two reviewers independently selected the studies, extracted the data and assessed risk of bias. Important AD cognitive scales as clinical efficacy outcomes were ADAS-cog, CDR and MMSE whereas edema, neoplasms and mortality were included as safety outcomes. A direct comparison meta-analysis using a random effect model and a network (direct and indirect) comparison was conducted to calculate mean differences in treatment effects, SUCRA and ranking probabilities for each medicine per safety and efficacy outcome. Quality of network results were assessed using GRADE methodology. Thirteen RCT-assessed patients with mild-to-moderate AD were included in the final analysis. The results showed that immunotherapies compared with placebo produced a statistically, but not clinically significant, improvement in ADAS-cog (MD=-0.39; 95% CI -0.42, -0.35, P=0.00) and MMSE. In terms of safety, the rate of ARIA-E was significantly higher with monoclonal antibodies. Solanezumab and AN1792 (vaccine) were the drugs of choice both from efficacy and safety perspectives. In terms of efficacy, the review showed a statistically, but not clinically significant, improvement in favor of immunotherapy versus placebo. Further clinical trials are required to demonstrate any cognitive benefits of immunotherapies in mild-to-moderate AD.

Effects of Home Photobiomodulation Treatments on Cognitive and Behavioral Function, Cerebral Perfusion, and Resting-State Functional Connectivity in Patients with Dementia: A Pilot Trial.

Objective: To examine the effects of transcranial and intranasal photobiomodulation (PBM) therapy, administered at home, in patients with dementia. Background: This study sought to replicate and build upon a previously published case series report describing improved cognitive function in five patients with mild-to-moderate dementia after 12 weeks of transcranial and intranasal near-infrared (NIR) PBM therapy. Materials and methods: Eight participants (mean age: 79.8 ± 5.8 years old) diagnosed with dementia by their physicians were randomized to 12 weeks of usual care (UC, n = 4) or home PBM treatments (n = 4). The NIR PBM treatments were administered by a study partner at home three times per week with the Vielight Neuro Gamma device. The participants were assessed with the Alzheimer's Disease Assessment Scale-cognitive (ADAS-cog) subscale and the Neuropsychiatric Inventory (NPI) at baseline and 6 and 12 weeks, and with arterial spin-labeled perfusion magnetic resonance imaging (MRI) and resting-state functional MRI at baseline and 12 weeks. Results: At baseline, the UC and PBM groups did not differ demographically or clinically. However, after 12 weeks, there were improvements in ADAS-cog (group × time interaction: F1,6 = 16.35, p = 0.007) and NPI (group × time interaction: F1,6 = 7.52, p = 0.03), increased cerebral perfusion (group × time interaction: F1,6 = 8.46, p < 0.03), and increased connectivity between the posterior cingulate cortex and lateral parietal nodes within the default-mode network in the PBM group. Conclusions: Because PBM was well tolerated and associated with no adverse side effects, these results support the potential of PBM therapy as a viable home treatment for individuals with dementia.

Clinical meaningfulness of Alzheimer's Disease Assessment Scale–Cognitive subscale change in relation to goal attainment in patients on cholinesterase inhibitors

IntroductionThe clinical meaningfulness of Alzheimer's Disease Assessment Scale–Cognitive subscale (ADAS-Cog) subscale change is disputed. We compared 2- to 4-point ADAS-Cog changes with changes in Goal Attainment Scaling (GAS) and everyday function across initial ADAS-Cog scores and treatment responses. MethodsThis exploratory analysis evaluated mild-moderate Alzheimer's disease patients treated with donepezil (12 months) or galantamine (8 months). Clinical meaningfulness was defined as concomitant ADAS-Cog and GAS changes of ±3 points and/or functional improvement. ResultsPatients with ≥3-point ADAS-Cog improvement significantly improved on GAS but not on standard tests of everyday function. ADAS-Cog “no change” (≤±3 points) was seen with mean GAS improvement. Initial ADAS-Cog improvement made endpoint improvement (ADAS-Cog 3 points and GAS 1 point) more likely (odds ratio = 6.9; 95% confidence interval = 2.5–19.5). In contrast, initial deterioration made endpoint improvement unlikely (0.33; 0.14–0.64). DiscussionADAS-Cog improvement and no change were each associated with GAS improvement. Initial ADAS-Cog worsening was unlikely to result in later improvement. Clinical trial registration numberISRCTN26167328.

71. Repetitive Transcranial Magnetic Stimulation (rTMS) applied with H-coil in Alzheimer’s disease: A placebo-controlled, double-blind, pilot study

Focal rTMS in Alzheimer’s disease (AD) revealed cognitive benefits. H-coil can depolarize deeper and wider structures compared with focal coils, thus targeting widespread networks involved in neurodegenerative disorders. We aimed to evaluate H-coil rTMS safety and efficacy in AD. Thirty AD subjects (70.21 ± 8.66 y.o.), randomized in real or sham groups, underwent 16 rTMS sessions (3 weekly for 4 weeks, 1 weekly for other 4 weeks), over fronto-parieto-temporal lobes at 10 Hz. Neuropsychological assessment was performed at baseline, after 4 weeks (4w), at the end of treatment (8w). Primary outcome was an improvement in Alzheimer’s disease scale-cognitive (ADAS-cog). No serious side effects were reported. Four subjects were excluded (1 acute myocardial infarction in the sham group, 1 misdiagnosis, 2 missing data), thus statistical analysis included 26 subjects. At 4w, percent ADAS-cog improvement from baseline (4 w%) was greater in the real compared with the sham group (p = 0.042). The relationship between baseline ADAS-cog and 4 w% differed between the two groups (p = 0.009), with higher improvement for less cognitively impaired subjects at baseline only in the real. These findings suggest that H-coil may be safe and effective in AD and that deep rTMS may better impact the course of the disease when administered at earlier stages.

ID 295 – Deep repetitive transcranial magnetic stimulation with the H-coil in Alzheimer’s disease: A placebo-controlled, double-blind study

Objective Focal rTMS in Alzheimer’s disease (AD) revealed cognitive benefits. H-coil depolarize deeper and wider structures compared with focal coils, maybe targeting widespread networks involved in neurodegenerative disorders. We explored H-coil safety and efficacy in AD. Methods Thirty AD subjects (70.21 ± 8.66 y.o.), randomized in real or sham groups, underwent 16 rTMS sessions (3/week for 4 weeks, 1/week for other 4 weeks), over fronto-parieto-temporal lobes (10 Hz). Neuropsychological assessment was performed at baseline, after 4 weeks (4 w), at the end (8 w). Primary outcome: improvement in Alzheimer’s disease Scale-cognitive (ADAS-cog). Four subjects were excluded (1 acute myocardial infarction in the sham group, 1 misdiagnosis, 2 missing data), thus statistical analysis included 26 subjects. Results No serious side effects were reported. At 4 w, percent ADAS-cog improvement from baseline (4 w%) was greater in the real compared with the sham group ( p = 0.042). The relationship between baseline ADAS-cog and 4 w% differed between the two groups ( p = 0.009), with higher improvement for less cognitively impaired subjects at baseline only after real stimulation. Conclusions Excitatory deep rTMS appears feasible in AD with a promising safety and efficacy profile and may better impact the course of the disease when administered at earlier stages.

Galantamine treatment in outpatients with mild Alzheimer's disease

To assess long-term effectiveness of galantamine in community-dwelling persons with mild Alzheimer's disease. Prospective open-label trial including patients with mild AD (NINCDS-ADRDA criteria) treated with galantamine for up to 36 months. Outcome parameters included ADAS-cog/11, Bayer-ADL scale (self- and caregivers' ratings), 10-item NPI and CGI-change, safety and tolerability measures. Data are presented based on ITT analyses (LOCF). Seventy-five patients (55% women; mean ADAS-cog 22.3; mean age 70.2 years) were treated with galantamine for approximately 36 months. About 60% (n=45) received a total daily dose of 24 mg galantamine at final visit. After 3, 6, and 12 months of treatment, mean improvements in ADAS-cog ranged between 2.2 and 3.0 points (all P<0.05). After 24-month treatment, ADAS-cog returned to baseline value and at 3-year follow-up, patient deteriorated on average by 2.9 points. There was significant improvement on the NPI scale between baseline and 3- to 12-month follow-up (all P<0.05) and at 3-year endpoint, a slight deterioration was noted. Activities of daily living (B-ADL) decreased significantly after 24 months in self-ratings and after 12 months in caregivers' ratings. Fifty-four patients reported at least one AE, most of them occurring during the first 2 years of treatment. Among the most frequently (>10%) reported AEs irrespective of causal relationship to study medication were nausea (17.3%), dizziness (12%), and vomiting (10.7%). Galantamine was generally safe and well tolerated during the 3-year observation period. Cognition, behavior, and activities of daily living improved during 12 months treatment. At 3-year follow-up, worsening in all outcomes was measured; however, cognition remained improved compared with an untreated population.

Association of the Recovery of Objective Abnormal Cerebral Perfusion With Neurocognitive Improvement After Carotid Revascularization

This study sought to report the effect of carotid artery stenting (CS) on neurocognitive function (NCF) in patients with severe carotid artery occlusive disease, depending on baseline brain perfusion status. The effect of CS on NCF has been controversial. We prospectively enrolled 61 patients with carotid artery disease (22 with occlusion, 39 with severe stenosis) in whom CS was attempted. Computed tomography perfusion and NCF assessments including Mini-Mental State Examination (MMSE), Alzheimer Disease Assessment Scale-Cognitive subscale (ADAS-Cog), verbal fluency, and Color Trails Test Parts 1 and 2 were applied before and 3 months after intervention. Successful recanalization was achieved in 14 of 22 occlusion patients (64%) and in all 39 severe stenosis patients. Two cases were excluded due to procedural cerebral complications. The patients were divided into 3 groups: group 1 (n= 8) consisted of patients with abnormal baseline ipsilateral cerebral perfusion in whom CS failed; group 2 (n=33) consisted of patients with abnormal baseline ipsilateral cerebral perfusion in whom CS was successful; andgroup 3 (n= 19) consisted of patients without abnormal baseline ipsilateral cerebral perfusion in whom CS was successful. The demographics and baseline NCF were similar among groups. Only in group 2 was there significant improvement in ADAS-Cog (pre-procedure median [interquartile range]: 6 [4 to 9] vs. post-procedure: 5 [3 to 7], p=0.002), MMSE (pre-procedure: 27 [25 to 28] vs. post-procedure: 28 [25 to 29], p= 0.004) and Color Trails Test Part 1 (pre-procedure: 100 [78.5 to 136.5] s vs. post-procedure: 97 [60 to 128.5] s, p= 0.003) after CS. Significant difference in changes from baseline was observed only in the Color Trails Test Part 1 among groups (group 1 vs. 2vs. 3: 1.5 [-14 to 11.5] vs.-12.5 [-36.5 to 0.5] vs.-0.5 [-11 to 27], p= 0.0159). Significant correlation between the change of ipsilateral brain perfusion and MMSE (r=-0.33, p= 0.01) was also identified. Successful CS for severe carotid stenosis/occlusion improves NCF, but only in patients with objective baseline abnormal cerebral perfusion.

Efficacy of a medical food on cognition in Alzheimer's disease: results from secondary analyses of a randomized, controlled trial.

To investigate the extent that baseline cognitive impairment and intake adherence affected the 13-item Alzheimer's Disease Assessment Scale - cognitive subscale (ADAS-cog) intervention response of a medical food in Alzheimer's Disease (AD) patients. DESIGN/SETTING/PARTICIPANTS /INTERVENTION/MEASUREMENTS: This analysis was performed on data from a proof-of-concept study, consisting of a 12-week, double-blind, randomized, controlled, multicenter trial, followed by a similarly designed 12-week extension study. Patients with mild AD (Mini-Mental State Examination [MMSE] score of 20-26) were randomized to receive active or control product as a 125 ml daily drink. One of the co-primary outcome measures was the 13-item ADAS-cog. In this analysis, the study population was divided into two subgroups: patients with 'low' baseline ADAS-cog scores (<25.0) and patients with 'high' baseline ADAS-cog scores (≥25.0). Repeated Measures Models (RMM) were used to determine the relationship between ADAS-cog score and intervention. A significant treatment effect (F[1,319]=4.0, p=0.046) was shown in patients with 'high' baseline ADAS-cog, but not in patients with 'low' baseline ADAS-cog (F[1,250]=1.25, p=0.265). Overall, intake adherence was significantly correlated with ADAS-cog improvement in the active product group (correlation coefficient=-0.260; p=0.019), but not the control group. These data indicate that baseline ADAS-cog significantly influenced the effect of Souvenaid intervention on ADAS-cog outcome. A higher intake of active study product was also associated with greater cognitive benefit. These findings highlight the potential benefits of Souvenaid in AD patients and warrant confirmation in larger, controlled studies.

A phase II trial of huperzine A in mild to moderate Alzheimer disease

Huperzine A is a natural cholinesterase inhibitor derived from the Chinese herb Huperzia serrata that may compare favorably in symptomatic efficacy to cholinesterase inhibitors currently in use for Alzheimer disease (AD). We assessed the safety, tolerability, and efficacy of huperzine A in mild to moderate AD in a multicenter trial in which 210 individuals were randomized to receive placebo (n = 70) or huperzine A (200 μg BID [n = 70] or 400 μg BID [n = 70]), for at least 16 weeks, with 177 subjects completing the treatment phase. The primary analysis assessed the cognitive effects of huperzine A 200 μg BID (change in Alzheimer's Disease Assessment Scale-cognitive subscale [ADAS-Cog] at week 16 at 200 μg BID compared to placebo). Secondary analyses assessed the effect of huperzine A 400 μg BID, as well as effect on other outcomes including Mini-Mental State Examination, Alzheimer's Disease Cooperative Study-Clinical Global Impression of Change scale, Alzheimer's Disease Cooperative Study Activities of Daily Living scale, and Neuropsychiatric Inventory (NPI). Huperzine A 200 μg BID did not influence change in ADAS-Cog at 16 weeks. In secondary analyses, huperzine A 400 μg BID showed a 2.27-point improvement in ADAS-Cog at 11 weeks vs 0.29-point decline in the placebo group (p = 0.001), and a 1.92-point improvement vs 0.34-point improvement in the placebo arm (p = 0.07) at week 16. Changes in clinical global impression of change, NPI, and activities of daily living were not significant at either dose. The primary efficacy analysis did not show cognitive benefit with huperzine A 200 μg BID. This study provides Class III evidence that huperzine A 200 μg BID has no demonstrable cognitive effect in patients with mild to moderate AD.

Long-Term Response to Galantamine in Relation to Short-Term Efficacy Data: Pooled Analysis in Patients with Mild to Moderate Alzheimers Disease

Background:This analysis aimed to identify an operational, clinically relevant definition of response achieved in short-term clinical trials to support the identification of patients with Alzheimer’s disease (AD) who would benefit most from long-term galantamine therapy.Methods:Data were analyzed from 6 randomized placebo-controlled trials of up to 6 months’ duration, which included patients with mild to moderate AD receiving maintenance doses of galantamine 16-24 mg/day, and from 12 open-label extensions (galantamine 24 mg/day maintenance therapy). Assessments included changes from baseline in the 11-item AD Assessment Scale-Cognitive subscale (ADAS-Cog 11).Results:Pooled analysis of the 5-6 month trial data showed that at the trial endpoint (2-5 months after reaching maintenance doses), the proportions of galantamine- (n=1,173) versus placebo-treated patients (n=801) with probable AD categorized according to “improved”, “stable” or “non-rapid decline” criteria, were 45.8% versus 27.2%, 59.5% versus 37.1%, and 87.6% versus 69.7%, respectively (observed cases analysis), whilst changes in ADAS-Cog 11 scores versus baseline were -4.9, -4.7 and -2.9 points, respectively, for “improved”, “stable” and “non-rapid decline” galantamine-treated patients (-1.5 points for galantamine recipients overall). “Improved” or “stable” galantamine-treated patients displayed mean improvement in ADAS-Cog 11 scores over baseline until 18 months after starting treatment, and attenuated deterioration thereafter; for galantamine-treated patients exhibiting “non-rapid decline”, mean ADAS-Cog 11 score returned to baseline after approximately 12 months.Conclusions:Patients who demonstrate improvement, stability, or limited cognitive decline 2-5 months after reaching maintenance doses of galantamine are more likely to experience continued benefit from long-term galantamine therapy.

Rivastigmine for cognitive impairment after spontaneous subarachnoid haemorrhage: a pilot study

Rivastigmine has been shown to be effective for patients with mild-to-moderate Alzheimer's disease. Its effect on cognitive impairment after aneurysmal subarachnoid haemorrhage has not been previously studied. The aim of the study is to evaluate the efficacy and safety of rivastigmine 3 mg/day over 12 weeks in patients with aneurysmal subarachnoid haemorrhage and persistent cognitive impairment. Twenty Chinese patients with spontaneous subarachnoid haemorrhage at least 9 months after the initial ictus, and with persistent cognitive impairment, were recruited. The primary outcome measure was Cognitive Subscale of Alzheimer Disease Assessment Scale (ADAS-cog) for global function; the secondary outcome measures were the Frontal Assessment Battery (FAB) for frontal lobe function and the Rivermead Behavioural Memory Test (RBMT) for prospective memory. Baseline cholinergic dysfunction (with pupillometry) was assessed for relationship with treatment efficacy. Sixteen of 20 (80%) patients completed the 12-week course of rivastigmine 1.5 mg twice daily. In comparison with the baseline assessment, ADAS-cog showed significant improvement after treatment (mean difference 6.5, 95% CI 3.5-9.5, P < 0.001); FAB and RBMT also showed significant improvement. Baseline cholinergic dysfunction (with pupillometry) was not correlated with improvement in ADAS-cog, FAB or RBMT. The use of rivastigmine was safe in patients with spontaneous subarachnoid haemorrhage and persistent cognitive impairment. A prospective double-blind placebo-controlled trial is required to establish the efficacy of rivastigmine for patients with spontaneous subarachnoid hemorrhage and persistent cognitive impairment and whether it can be translated to improvement in instrumental activity of daily living and quality of life.

The ADAS‐cog and clinically meaningful change in the VISTA clinical trial of galantamine for Alzheimer's disease

A minimum 4-point change at 6 months on the Alzheimer's disease assessment scale-cognitive subscale (ADAS-cog) is deemed clinically important, but this cut-point has been little studied in relation to clinical meaningfulness. In an investigator-initiated, clinical trial of galantamine, we investigated the extent to which a 4-point change classifies goal attainment by individual patients. Secondary analysis of the video imaging synthesis of treating Alzheimer's disease (VISTA) study: a 4-month, multi-centre, parallel-group, double-blind, placebo-controlled, trial of galantamine in 130 mild-moderate Alzheimer's disease patients (4-month open-label follow-up). ADAS-cog responses at 6 months were compared with outcomes on three clinical measures: clinician's interview based impression of change-plus caregiver input (CIBIC+), patient/carer-goal attainment scaling (PGAS) and clinician-GAS (CGAS). Thirty-seven of 99 patients improved by > or = 4 points on the ADAS-cog at 6 months, and 16/99 showed > or = 4-point worsening. ADAS-cog change scores correlated notionally to modestly with changes on the CGAS (r = -0.31), the PGAS (r = -0.29) and the CIBIC+ (r = 0.31). As a group, patients with ADAS-cog improvement were significantly more likely to improve on the clinical measures; those who worsened showed non-significant clinical decline. Individually, about half were misclassified in relation to each clinical measure; often when the ADAS-Cog detected 'no change', clinically meaningful effects could be detected. Even so, no ADAS-Cog cut-point optimally classified patients' clinical responses. A 4-point ADAS-cog change at 6 months is clinically meaningful for groups. Substantial individual misclassification between the ADAS-cog and clinical measures suggests no inherent meaning to a 4-point ADAS-cog change for a given patient.

The effects of omega-3 fatty acids monotherapy in Alzheimer's disease and mild cognitive impairment: A preliminary randomized double-blind placebo-controlled study

A 24-week, randomized, double-blind placebo-controlled study was carried out to test the feasibility of using omega-3 polyunsaturated fatty acids (PUFAs) monotherapy in people with cognitive impairment and to explore its effects on cognitive function and general clinical condition in these participants. Twenty three participants with mild or moderate Alzheimer’s disease and twenty three with mild cognitive impairment were randomized to receive omega-3 PUFAs 1.8 g/day or placebo (olive oil). The data of 35 (76%) participants with at least one post-treatment visit was analyzed. There were no severe adverse effects in either group and it suggests that omega-3 PUFAs were well tolerable in this population. The treatment group showed better improvement on the Clinician’s Interview-Based Impression of Change Scale (CIBIC-plus) than those in the placebo group over the 24 week follow-up ( p = 0.008). There was no significant difference in the cognitive portion of the Alzheimer’s Disease Assessment Scale (ADAS-cog) change during follow-up in these two groups. However, the omega-3 fatty acids group showed significant improvement in ADAS-cog compared to the placebo group in participants with mild cognitive impairment ( p = 0.03), which was not observed in those with Alzheimer’s disease. Higher proportions of eicosapentaenoic acid on RBC membranes were also associated with better cognitive outcome ( p = 0.003). Further studies should be considered with a larger-sample size, diet registration, higher dosages, comparisons between different combinations of PUFAs, and greater homogeneity of participants, especially those with mild Alzheimer’s disease and mild cognitive impairment.

The clinical meaningfulness of ADAS-Cog changes in Alzheimer's disease patients treated with donepezil in an open-label trial

BackgroundIn 6-month anti-dementia drug trials, a 4-point change in the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) is held to be clinically important. We examined how this change compared with measures of clinical meaningfulness.MethodsThis is a secondary analysis of a 12 month open-label study of 100 patients (71 women) diagnosed with mild to moderate AD treated with 5–10 mg of donepezil daily. We studied the observed case, 6-month change from baseline on the ADAS-Cog, the Clinician's Interview Based Impression of Change-Plus Caregiver Input (CIBIC-Plus), patient-Goal Attainment Scaling (PGAS) and clinician-GAS (CGAS).ResultsAt 6 months, donepezil-treated patients (n = 95) were more likely to show no change (+/- 3 points) on the ADAS-Cog (56%) than to improve (20%) or decline (24%) by 4-points. ADAS-Cog change scores were little correlated with other measures: from -0.09 for PGAS to 0.27 for the CIBIC-Plus. While patients who improved on the ADAS-Cog were less likely to decline on the clinical measures (26%), 43% of patients who declined on the ADAS-Cog improved on at least two of the clinical measures.ConclusionThe ADAS-Cog did not capture all clinically important effects. In general, ADAS-Cog improvement indicates clinical improvement, whereas many people with ADAS-Cog decline do not show clinical decline. The open-label design of this study does not allow us to know whether this is a treatment effect, which requires further investigation.

Cholinesterase inhibitors for Parkinson's disease dementia

The loss of cholinergic, dopaminergic and noradrenergic innervations seen in Parkinson's Disease Dementia (PDD) suggest a potential role for cholinesterase inhibitors. Concerns have been expressed about a theoretical worsening of Parkinson's disease related symptoms particularly movement symptoms. To assess the efficacy, safety, tolerability and health economic data relating to the use of cholinesterase inhibitors in PDD. The trials were identified from the Specialized Register of the Cochrane Dementia and Cognitive Improvement Group on 19 April 2005 using the search term parkinson*This register contains records from major health care databases and many ongoing trial databases and is updated regularly.Comprehensive searches of abstracts from major scientific meetings were performed. Pharmaceutical companies were approached for information regarding additional and ongoing studies. Randomized, double-blind, placebo-controlled studies assessing the effectiveness of cholinesterase inhibitors in PDD. Inclusion and exclusion criteria were stated to limit bias. Two reviewers (IM, CF) independently reviewed the quality of the studies utilising criteria from the Cochrane Collaboration Handbook. Medications were examined separately and as a group. The outcome measures assessed were in the following domains: neuropsychiatric features, cognition, global impression, daily living activities, quality of life, burden on caregiver, Parkinsonian related symptoms, treatment acceptability as determined by withdrawal from trials, safety as determined by the frequency of adverse events, institutionalisation, death and health economic factors. A detailed and systematic search of relevant databases identified one published randomized, double-blind, placebo-controlled study (Emre 2004) involving 541 patients that compared rivastigmine with placebo. Rivastigmine produced statistically significant improvements in several outcome measures. On the primary cognitive measure, the ADAS-Cog, rivastigmine was associated with a 2.80 point ADAS-Cog improvement [WMD -2.80, 95% Cl -4.26 to -1.34, P = 0.0002] and a 2.50 point ADCS-ADL improvement [95% Cl 0.43 to 4.57, P = 0.02] relative to placebo. Clinically meaningful (moderate or marked) improvement occurred in 5.3% more patients on rivastigmine, and meaningful worsening occurred in 10.1% more patients on placebo. Tolerability appeared to be a significant issue. Significantly more patients on rivastigmine dropped out of the study due to adverse events [62/362 versus 14/179, OR 2.44, 95% Cl 1.32 to 4.48, P = 0.004]. Nausea [20/179 versus 105/362, OR 3.25, 95% Cl 1.94 to 5.45, P < 0.00001], tremor [7/179 versus 37/362, OR 2.80, 95% Cl 1.22 to 6.41, P = 0.01] and in particular vomiting [3/179 versus 60/362, OR 11.66, 95% Cl 3.60 to 37.72, P < 0.0001] were significantly more common with rivastigmine. However, significantly fewer patients died on rivastigmine than placebo [4/362 versus 7/179, OR 0.27, 95% CI 0.08 to 0.95, P = 0.04] Rivastigmine appears to improve cognition and activities of daily living in patients with PDD. This results in clinically meaningful benefit in about 15% of cases. There is a need for more studies utilising pragmatic measures such as time to residential care facility and both patient and carer quality of life assessments. Future trials should involve other cholinesterase inhibitors, utilise tools to analyse the data that limit any bias and measure health economic factors. It is unlikely that relying solely on the last observation carried forward (LOCF) is sufficient. Publication of the observed case data in the largest trial would assist (Emre 2004). Adverse events were associated with the cholinergic activity of rivastigmine, but may limit patient acceptability as evidenced by the high drop out rate in the active arm.

One-year treatment of Alzheimer's disease with acetylcholinesterase inhibitors: improvement on ADAS-cog and TMT A, no change or worsening on other tests

The aim of this study was to assess cognitive functioning measured by selected psychometric and neuropsychological tools in patients with Alzheimer's disease (AD) after 1-year treatment with acetylcholinesterase inhibitors. Seventy-six patients (22 male and 54 female) with a mild to moderate stage of AD, aged 56-86 (mean 68) years, were treated. Forty-seven received donepezil (mean dose 9.3 mg/d) and 29 rivastigmine (mean dose 8.5 mg/d). Cognitive measurements included: the mini mental state examination (MMSE), the Alzheimer disease assessment scale-cognitive (ADAS- cog), the trail making test (TMT) and the Stroop color word interference test. The assessments were made before and after 3, 6 and 12 months of treatment. A significant improvement in ADAS-cog (p < 0.001, 83% of patients improved) and a worsening in MMSE (84% of patients worsened, p < 0.01 after 6 and 12 months) was noted after the 1 year treatment. A majority of patients (57%) improved in the TMT-A (p < 0.001), measuring psychomotor speed and worsened in the TMT-B (p < 0.01, after 12 months), and Stroop B test (p < 0.001), measuring working memory and executive functions, 53% and 61%, respectively. Most patients (83%) did not change their performance in the Stroop A (improvement after 3 months, p < 0.001, worsening after 6 and 12 months p < 0.01) test measuring verbal abilities, after 1 year treatment. The results obtained suggest that the treatment with cholinergic drugs may improve global cognitive functioning (ADAS-cog) and psychomotor speed (TMT A), however, such treatment is unable to prevent the deterioration of working memory and executive functions.

Acetylcholinesterase inhibitors in Alzheimer's disease.

Alzheimer’s Disease (AD) is the most common single cause of dementia in our ageing society. Traditionally thought of as an untreatable degenerative condition, recent advances in drug therapy have challenged this view. The disease is characterised by an insidious decline in cognitive and non-cognitive function. Classically, short and long-term memory is impaired while language skills, concentration and attention are often affected. This results in impaired ability to learn and retain new skills as well as the loss of existing ones. Non-cognitive function is the global term used to describe problems such as depression, agitation, personality changes, delusions and hallucinations. These factors have a significant impact on patient behaviour and a very real impact on the quality of life for both patients and caregivers. Diagnosis of AD is clinically based, and using the NINCDS-ADRDA criteria (Table 1) [1], a diagnosis of probable or possible AD can be made. Definitive diagnosis relies on pathological confirmation, which in the majority of cases is rarely completed. With the development of AD specific treatments, definition of AD from other types of dementia is very important. Table 1 NINCDS-ADRDA Criteria for clinical diagnosis of Alzheimer’s disease. Pathogenesis The pathogenesis of AD has not yet been elucidated. It is widely accepted that a combination of genetic susceptibility factors and environmental triggers are responsible for late onset sporadic AD, the most common form of the disease. An understanding of the disease mechanism remains elusive, and is the key to developing a disease modifying agent. Currently, it is proposed that beta amyloid protein, abnormal tau protein or possibly both play key factors in the development of disease. It has been widely postulated that oxidative damage and a slow inflammatory process are two possible mechanisms involved. As yet, no product with proven disease modifying properties is available, and current treatments offer symptomatic benefit only. The development of acetylcholinesterase (AChe) inhibitor drugs has followed the finding that cholinergic pathways in the cerebral cortex and basal forebrain are compromised in AD [2] and the resultant cholinergic deficit contributes to the cognitive impairment of these patients [3]. Although many believe this ‘cholinergic hypothesis’ to be important, others feel it represents a less significant component of the disease process [4]. Many other neurotransmitters are affected in AD, and the relative importance of each in relation to clinical findings has not been fully elucidated. Initial work focused on the use of acetylcholine precursors, using a similar rationale to dopamine therapy in Parkinson’s disease. A series of small trials using precursors such as choline and phosphatidylcholine showed no reliable improvement in cognitive function, with only 10 out of 43 trials reporting any positive effect [5]. There has been renewed interest in muscarinic agonists drugs, which when first introduced, had major problems with adverse cholinergic effects. Better understanding of the molecular pathology of muscarinic receptors and their subtypes has led to the development of more specific agonists. Drugs such as xanomeline, milameline, and civimeline have reached clinical trials, and the improvements seen in cognitive function are reviewed by Avery et al. [6]. There are also claims that these drugs have disease modifying properties, with effects on APP processing and tau phosphorylation. Muscarinic agonists remain in trial, but have yet to fulfil their potential in AD treatment. The only group of drugs currently licensed for AD treatment is the AChe inhibitors, which act through inhibition of the enzyme acetylcholinesterase (AChe), responsible for the breakdown of ACh in the neural synapse. A meta-analysis of the early AChe inhibitor treatments was encouraging [7] and these proceeded to larger placebo controlled double-blind trials.