Donanemab in Japanese Patients with Early Alzheimer's Disease: Subpopulation Analysis of the TRAILBLAZER-ALZ 2 Randomized Trial.

INTRODUCTION: Donanemab, a monoclonal antibody directed against an insoluble, modified, N-terminal truncated form of amyloid beta, demonstrated efficacy and safety in patients with early, symptomatic Alzheimer's disease (AD) in the phase 3 TRAILBLAZER-ALZ 2 trial. Here, we report clinical outcomes, biomarkers, and safety results for the Japanese subpopulation. METHODS: TRAILBLAZER-ALZ 2 (N = 1736) was conducted in eight countries, including Japan (enrollment June 2020-November 2021; database lock April 2023). Participants (60-85 years) with early, symptomatic AD (mild cognitive impairment/mild dementia), Mini-Mental State Examination score 20-28, and confirmed amyloid and tau pathology were randomized 1:1 (stratified by tau status) to intravenous donanemab (700 mg for three doses, then 1400 mg/dose) or placebo every 4 weeks for 72 weeks. Primary outcome was change from baseline to week 76 in integrated Alzheimer's Disease Rating Scale (iADRS) score. Other outcomes included clinical measures of cognitive and functional impairment, biomarkers, and safety. RESULTS: Of 88 Japanese participants (43 placebo, 45 donanemab), 7 in each group discontinued. Least-squares mean (LSM) change from baseline in iADRS score at week 76 was smaller with donanemab than with placebo in the combined (low-medium tau and high tau) and low-medium tau (N = 76) subpopulations (LSM change difference: 4.43 and 3.99, representing 38.8% and 40.2% slowing of disease progression, respectively). Slowing of AD progression with donanemab was also observed for other clinical outcomes. Marked decreases in amyloid plaque and plasma phosphorylated tau 217 were observed; amyloid clearance (< 24.1 Centiloids) was observed in 83.3% of the combined donanemab and 0% of the combined placebo groups. Amyloid-related imaging abnormalities of edema/effusions occurred in ten (22.2%) donanemab-treated participants (one [2.2%] symptomatic) and one (2.3%) placebo-treated participant. CONCLUSIONS: The overall efficacy and safety of donanemab in Japanese participants were similar to the global TRAILBLAZER-ALZ 2 population. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT04437511.

Efficacy and safety of donepezil in patients with dementia with Lewy bodies: results from a 12-week multicentre, randomised, double-blind, and placebo-controlled phase IV study.

BACKGROUND: Donepezil has been approved in Japan for the treatment of dementia with Lewy bodies (DLB) based on clinical trials showing its beneficial effects on cognitive impairment. This phase IV study evaluated the efficacy of donepezil by focusing on global clinical status during a 12-week double-blind phase. METHODS: Patients with probable DLB were randomly assigned to the placebo (n = 79) or 10 mg donepezil (n = 81) groups. The primary endpoint was changes in global clinical status, assessed using the Clinician's Interview-Based Impression of Change plus Caregiver Input (CIBIC-plus). We also assessed four CIBIC-plus domains (general condition, cognitive function, behaviour, and activities of daily living) and changes in cognitive impairment and behavioural and neuropsychiatric symptoms measured using the Mini-Mental State Examination (MMSE) and the Neuropsychiatric Inventory (NPI), respectively. RESULTS: Although donepezil's superiority was not shown in the global clinical status, a significant favourable effect was detected in the cognitive domain (P = 0.006). MMSE scores improved in the donepezil group after adjustments in post hoc analysis (MMSE mean difference, 1.4 (95% confidence interval (CI), 0.42-2.30), P = 0.004). Improvements in NPIs were similar between the groups (NPI-2: -0.2 (95% CI, -1.48 to 1.01), P = 0.710; NPI-10: 0.1 (95% CI, -3.28 to 3.55), P = 0.937). CONCLUSION: The results support the observation that the efficacy of 10 mg donepezil in improving cognitive function is clinically meaningful in DLB patients. The evaluation of global clinical status might be affected by mild to moderate DLB patients enrolled in this study. No new safety concerns were detected.

Lecanemab in Early Alzheimer's Disease.

BACKGROUND: The accumulation of soluble and insoluble aggregated amyloid-beta (Aß) may initiate or potentiate pathologic processes in Alzheimer's disease. Lecanemab, a humanized IgG1 monoclonal antibody that binds with high affinity to Aß soluble protofibrils, is being tested in persons with early Alzheimer's disease. METHODS: We conducted an 18-month, multicenter, double-blind, phase 3 trial involving persons 50 to 90 years of age with early Alzheimer's disease (mild cognitive impairment or mild dementia due to Alzheimer's disease) with evidence of amyloid on positron-emission tomography (PET) or by cerebrospinal fluid testing. Participants were randomly assigned in a 1:1 ratio to receive intravenous lecanemab (10 mg per kilogram of body weight every 2 weeks) or placebo. The primary end point was the change from baseline at 18 months in the score on the Clinical Dementia Rating-Sum of Boxes (CDR-SB; range, 0 to 18, with higher scores indicating greater impairment). Key secondary end points were the change in amyloid burden on PET, the score on the 14-item cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-cog14; range, 0 to 90; higher scores indicate greater impairment), the Alzheimer's Disease Composite Score (ADCOMS; range, 0 to 1.97; higher scores indicate greater impairment), and the score on the Alzheimer's Disease Cooperative Study-Activities of Daily Living Scale for Mild Cognitive Impairment (ADCS-MCI-ADL; range, 0 to 53; lower scores indicate greater impairment). RESULTS: A total of 1795 participants were enrolled, with 898 assigned to receive lecanemab and 897 to receive placebo. The mean CDR-SB score at baseline was approximately 3.2 in both groups. The adjusted least-squares mean change from baseline at 18 months was 1.21 with lecanemab and 1.66 with placebo (difference, -0.45; 95% confidence interval [CI], -0.67 to -0.23; P<0.001). In a substudy involving 698 participants, there were greater reductions in brain amyloid burden with lecanemab than with placebo (difference, -59.1 centiloids; 95% CI, -62.6 to -55.6). Other mean differences between the two groups in the change from baseline favoring lecanemab were as follows: for the ADAS-cog14 score, -1.44 (95% CI, -2.27 to -0.61; P<0.001); for the ADCOMS, -0.050 (95% CI, -0.074 to -0.027; P<0.001); and for the ADCS-MCI-ADL score, 2.0 (95% CI, 1.2 to 2.8; P<0.001). Lecanemab resulted in infusion-related reactions in 26.4% of the participants and amyloid-related imaging abnormalities with edema or effusions in 12.6%. CONCLUSIONS: Lecanemab reduced markers of amyloid in early Alzheimer's disease and resulted in moderately less decline on measures of cognition and function than placebo at 18 months but was associated with adverse events. Longer trials are warranted to determine the efficacy and safety of lecanemab in early Alzheimer's disease. (Funded by Eisai and Biogen; Clarity AD ClinicalTrials.gov number, NCT03887455.).

Efficacy, Safety, and Tolerability of Switching from Oral Cholinesterase Inhibitors to Rivastigmine Transdermal Patch with 1-Step Titration in Patients with Mild to Moderate Alzheimer's Disease: A 24-Week, Open-Label, Multicenter Study in Japan.

BACKGROUND: Few studies have investigated treatment options for patients with Alzheimer's disease (AD) showing a poor response to oral cholinesterase inhibitors (ChEIs) in Japan. OBJECTIVE: To investigate the efficacy and safety of switching from oral ChEIs to rivastigmine transdermal patch in patients with AD. METHODS: In this multicenter, open-label, phase IV study in outpatient clinics in Japan, patients with mild-moderate AD who had a poor response to or experienced difficulty in continuing donepezil or galantamine were switched to rivastigmine transdermal patch (5 cm2; loaded dose 9 mg, delivery rate 4.6 mg/24 h) with a 1-step titration in week 4 (10 cm2; loaded dose 18 mg, delivery rate 9.5 mg/24 h), which was continued for 4 weeks in the titration period and 16 weeks in a maintenance period. The primary endpoint was the change in Mini-Mental State Examination (MMSE) total score from baseline to week 24. RESULTS: A total of 118 patients were enrolled and switched to rivastigmine, of which 102 completed the 24-week study. The MMSE total score was essentially unchanged during the study, with a least-square mean change (SD) of -0.35 (2.64) at week 24 (p = 0.1750). Exploratory analysis with a mixed-effect model comparing changes in MMSE between the pre- and post-switch periods suggested that switching to rivastigmine prevented a worsening of MMSE. Application site skin reactions/irritations occurred in 30.5% of patients overall, in 22.0% in the 8-week titration period, and in 10.2% in the 16-week maintenance period. CONCLUSION: Within-class switching from an oral ChEI to rivastigmine transdermal patch might be an efficacious and tolerable option for AD patients showing a poor or limited response to a prior oral ChEI.

Bapineuzumab for mild to moderate Alzheimer's disease in two global, randomized, phase 3 trials.

BACKGROUND: Our objective was to evaluate the efficacy (clinical and biomarker) and safety of intravenous bapineuzumab in patients with mild to moderate Alzheimer's disease (AD). METHODS: Two of four phase 3, multicenter, randomized, double-blind, placebo-controlled, 18-month trials were conducted globally: one in apolipoprotein E ε4 carriers and another in noncarriers. Patients received bapineuzumab 0.5 mg/kg (both trials) or 1.0 mg/kg (noncarrier trial) or placebo every 13 weeks. Coprimary endpoints were change from baseline to week 78 on the 11-item Alzheimer's Disease Assessment Scale-Cognitive subscale and the Disability Assessment for Dementia. RESULTS: A total of 683 and 329 patients completed the current carrier and noncarrier trials, respectively, which were terminated prematurely owing to lack of efficacy in the two other phase 3 trials of bapineuzumab in AD. The current trials showed no significant difference between bapineuzumab and placebo for the coprimary endpoints and no effect of bapineuzumab on amyloid load or cerebrospinal fluid phosphorylated tau. (Both measures were stable over time in the placebo group.) Amyloid-related imaging abnormalities with edema or effusion were confirmed as the most notable adverse event. CONCLUSIONS: These phase 3 global trials confirmed lack of efficacy of bapineuzumab at tested doses on clinical endpoints in patients with mild to moderate AD. Some differences in the biomarker results were seen compared with the other phase 3 bapineuzumab trials. No unexpected adverse events were observed. TRIAL REGISTRATION: Noncarriers (3000) ClinicalTrials.gov identifier NCT00667810 ; registered 24 Apr 2008. Carriers (3001) ClinicalTrials.gov identifier NCT00676143 ; registered 2 May 2008.

Adequacy of Using Consensus Guidelines for Diagnosis of Dementia with Lewy Bodies in Clinical Trials for Drug Development.

BACKGROUND/AIMS: To evaluate the adequacy of using the consensus diagnostic criteria for dementia with Lewy bodies (DLB) to recruit patients with homogeneous characteristics in future clinical trials, where multiple departments of multinational centres are expected to participate with a long enrolment period, and additionally, to contribute to the possible future criteria revision. METHODS: Using data from 2 trials of donepezil for DLB, conducted 3 years apart, characteristics in patients with probable DLB were analysed and compared between studies and between psychiatric and neurological centres. RESULTS: In 273 patients (phase II: 135, phase III: 138; psychiatric: 73, neurological: 184), clinical characteristics overall were very similar between studies, and between specialty centres, excluding distinctive parkinsonism in the neurological versus psychiatric centres: incidence of parkinsonism (91.8 vs. 71.2%, p < 0.001), Hoehn and Yahr stage (III: 55.0 vs. 21.2%, p < 0.001), and concomitant anti-Parkinson medication (24.5 vs. 11.0%, p = 0.017). Rapid eye movement sleep behaviour disorder, depression, and delusion, suggestive or supportive features, were observed in 35-40%. Additionally, a high prevalence (55.3%) of anxiety was observed. CONCLUSION: Employing the consensus criteria is adequate to enrol homogeneous DLB patients into future clinical trials regardless of the specialty of centres and time. Further discussion could involve adding anxiety to future criteria.

Relationship between neuronal loss and tangle formation in neurons and oligodendroglia in progressive supranuclear palsy.

Progressive supranuclear palsy (PSP) is a progressive degenerative disorder characterized by neuronal loss, gliosis and abnormal fibril formation of abnormally phosphorylated tau protein in neurons and glia cells, but the cause is not clear at present. For the purpose of clarifying the pathological significance of accumulation of tau protein in neurons and oligodendroglia in PSP, we morphologically classified neurofibrillary tangles (NFT) and coiled bodies (CB) in oligodendroglia in three PSP brains into four stages, using double staining for immunohistochemistry with AT8 antibody and modified Gallyas-Braak (GB) staining. AT8-positive neurons without abnormal fibril structure with GB staining were classified as stage I, AT8-positive neurons containing a few fibril structures with GB staining were classified stage II, AT8-positive neurons containing mature fibril structures were classified as stage III, and AT8 negative neurons containing abnormal fibril structures stained only with GB staining were classified as stage IV (ghost tangles). These stages were also assessed for CB. Then we counted the number of cells of each stage in various brain regions to investigate the relationship of NFT and CB with neuronal loss and gliosis. The results showed that there were very few stage IV NFT and CB, which reflect cell death, but that stage III NFT and CB were abundant. Moreover, CB were abundant in regions with severe neuronal loss. These results suggest that appearance of CB is closely associated with degenerative regions.

Autopsy case of pure akinesia showing pallidonigro-luysian atrophy.

A 60-year-old man developed levodopa-resistant pure akinesia. The patient gradually became more akinetic without accompanying gaze palsies, nuchal dystonia, or other parkinsonian features such as rigidity or tremor. At the age of 71, he died of bronchopneumonia. Neuropathologically, bilateral marked neuronal loss and gliosis were restrictedly observed in the globus pallidus, substantia nigra and corpus luysii, whereas mild gliosis without neuronal loss was found in the brain stem. With Gallyas-Braak silver stain, numerous argyrophilic fibrous structures partly surrounding glial nuclei were observed in the three major affected regions. With Bodian stain, however, they were rarely recognized. The structures were partly positive for tau protein. Rare neurofibrillary tangles were found in the three areas and brain stem. They were relatively more numerous but still sparse in the hippocampus and the parahippocampus. The present case was diagnosed as having pallidonigro-luysian atrophy based on two characteristic findings: (i) the distribution of lesions showing neuronal loss with gliosis; and (ii) significant presence of tau-positive argyrophilic fibrous structures related to glia but with the absence of neurofibrillary tangles in the major affected regions and the brain stem. As our present case uniquely showed pure akinesia for the whole clinical course, it is noteworthy to report it here with a full neuropathological evaluation. In addition, a moderate number of diffuse plaques positive for beta-amyloid were distributed in the thalamus.

Magnetization transfer measurements of brain structures in patients with multiple system atrophy.

To determine whether magnetization transfer imaging (MTI) demonstrates abnormalities in the brain structures of patients with multiple system atrophy (MSA), we examined 12 patients with clinically probable MSA and 11 control subjects. We calculated magnetization transfer ratios (MTRs) using region of interest analysis from MTI and assessed abnormal signal changes on T2-weighted images. MTRs of the base of the pons, middle cerebellar peduncle, putamen, and white matter of the precentral gyrus were significantly lower in the MSA patients than in the controls. Abnormal signal changes on T2-weighted images were observed in the base of the pons (n = 6), middle cerebellar peduncle (n = 7), and putamen (n = 7). MTRs of regions with abnormal signals were significantly lower than those of regions without abnormal signals and those in the controls. Even the MTRs of the regions without abnormal signals were lower than those in the controls. MTRs of the pyramidal tract, including white matter of the precentral gyrus, posterior limb of the internal capsule, cerebral peduncle, and base of the pons, were significantly lower in patients with pyramidal tract sign (n = 7) than in the controls. Patients with asymmetrical parkinsonism (n = 5) showed significantly lower MTRs in the putamen contralateral to the predominant side of parkinsonian symptoms than the ipsilateral side, although asymmetry of abnormal signal changes on T2-weighted images was not evident in more than half of those patients. This study showed that MTI demonstrates abnormalities in the brains of patients with MSA that seem to reflect underlying pathological changes and that the pathological changes detected by MTI seem to give rise to clinical symptoms. This study also showed that the abnormalities are detected more sensitively and over a larger area by MTI than by conventional magnetic resonance imaging.

[A case of late onset mitochondrial neuromyopathy].

A 68-year-old woman was admitted with dysesthesia on both soles, hands and buttocks. She first noticed the dysesthesia in the left first toe two years before admission. One year before admission, serum creatine kinase and lactate dehydrogenase levels were elevated but she had no clinical symptoms suggesting myopathy. Nerve conduction study showed no apparent abnormalities, and an electromyogram showed mild myogenic change. Computed tomography of the muscle showed fatty degeneration of the trunk, major gluteus muscle, and biceps femoris muscle and atrophic change of the biceps femoris muscle. Muscle biopsy revealed a slight variation in fiber size, the presence of cytochrome c oxidase (CCO)-negative fibers by CCO staining, ragged-red fibers by Gomori trichrome staining, and mild denervation fiber by neuron specific enolase (NSE) staining. Analysis of her mitochondrial DNA (mtDNA) revealed a large deletion of mtDNA (approximately 8.5 Kb), and mitochondrial neuromyophy was diagnosed. The frequency of mtDNA deletion increases with aging. Although her mtDNA abnormality was compatible with chronic progressive external ophthalmoplegia (CPEO), we speculate that the aging process may be contributed to the mtDNA abnormality, which would be related to the late onset of her symptoms. As the phenotype of this mitochondrial disorder shows a wide variation and mtDNA abnormality is more frequent among elderly people, we should consider the possibility of mitochondrial disorders even in elderly people.

[An elderly case of microscopic polyangiitis following bronchial asthma].

A 78-year-old woman who had bronchial asthma for 15 years developed dysesthesia, neuralgia, muscle weakness and atrophy in both feet and her left hand. Prednisolone (maximum dose 80 mg) was not effective, and she displayed gait disturbance. Laboratory findings showed leukocytosis (neutrophils dominant), renal dysfunction, elevation of CRP and positive P-ANCA. Biopsy revealed vasculitis, and reduced density of myelinated fibers. Although steroid pulse therapy improved neuralgia and renal dysfunction, severe disability of motor function and sensory disturbance still remained. Vasculitis syndrome following bronchial asthma indicated Churg-Strauss syndrome (CSS), while severe renal dysfunction and lack of eosinophilia were symptoms compatible with microscopic polyangiitis (MPA). The present case showed properties of both MPA and CSS.