Repurposing bromocriptine for Aβ metabolism in Alzheimer’s disease (REBRAnD) study : randomised placebo-controlled double-blind comparative trial and open-label extension trial to investigate the safety and efficacy of bromocriptine in Alzheimer’s disease with presenilin 1 (PSEN1) mutations

Introduction Alzheimer’s disease (AD) is one of the most common causes of dementia. Pathogenic variants in the presenilin 1 (PSEN1) gene are the most frequent cause of early-onset AD. Medications for patients with AD bearing PSEN1 mutation (PSEN1-AD) are limited to symptomatic therapies and no established radical treatments are available. Induced pluripotent stem cell (iPSC)-based drug repurposing identified bromocriptine as a therapeutic candidate for PSEN1-AD. In this study, we used an enrichment strategy with iPSCs to select the study population, and we will investigate the safety and efficacy of an orally administered dose of bromocriptine in patients with PSEN1-AD. Methods and analysis This is a multicentre, randomised, placebo-controlled trial. AD patients with PSEN1 mutations and a Mini Mental State Examination-Japanese score of ≤25 will be randomly assigned, at a 2:1 ratio, to the trial drug or placebo group (≥4 patients in TW-012R and ≥2 patients in placebo). This clinical trial consists of a screening period, double-blind phase (9 months) and extension phase (3 months). The double-blind phase for evaluating the efficacy and safety is composed of the low-dose maintenance period (10 mg/day), high-dose maintenance period (22.5 mg/day) and tapering period of the trial drug. Additionally, there is an open-labelled active drug extension period for evaluating long-term safety. Primary outcomes are safety and efficacy in cognitive and psychological function. Also, exploratory investigations for the efficacy of bromocriptine by neurological scores and biomarkers will be conducted. Ethics and dissemination The proposed trial is conducted according to the Declaration of Helsinki, and was approved by the Institutional Review Board (K070). The study results are expected to be disseminated at international or national conferences and published in international journals following the peer-review process

The feasibility of white matter volume reduction analysis using SPM8 plus DARTEL for the diagnosis of patients with clinically diagnosed corticobasal syndrome and Richardson’s syndrome

Purpose: Diagnosing corticobasal degeneration (CBD) and progressive supranuclear palsy (PSP) is often difficult due to the wide variety of symptoms and overlaps in the similar clinical courses and neurological findings. The purpose of this study was to evaluate the utility of white matter (WM) atrophy for the diagnosis of patients with clinically diagnosed CBD (corticobasal syndrome, CBS) and PSP (Richardson’s syndrome, RS). Methods: We randomly divided the 3D T1-weighted MR images of 18 CBS patients, 33 RS patients, and 32 age-matched controls into two groups. We obtained segmented WM images in the first group using Voxel-based specific regional analysis system for Alzheimer’s disease (VSRAD) based on statistical parametric mapping (SPM) 8 plus diffeomorphic anatomical registration through exponentiated Lie algebra. A target volume of interest (VOI) for disease-specific atrophy was subsequently determined in this group using SPM8 group analyses of WM atrophy between patients groups and controls. We then evaluated the utility of these VOIs for diagnosing CBS and RS patients in the second group. Z score values in these VOIs were used as the determinant in receiver operating characteristic (ROC) analyses. Results: Specific target VOIs were determined in the bilateral frontal subcortical WM for CBS and in the midbrain tegmentum for RS. In ROC analyses, the target VOIs of CBS and RS compared to those of controls exhibited an area under curve (AUC) of 0.99 and 0.84, respectively, which indicated an adequate diagnostic power. The VOI of CBS revealed a higher AUC than that of RS for differentiating between CBS and RS (AUC, 0.75 vs 0.53). Conclusions: Bilateral frontal WM volume reduction demonstrated a higher power for differentiating CBS from RS. This VOI analysis is useful for clinically diagnosing CBS and RS

Amyloid β accumulation assessed with ¹¹C-Pittsburgh compound B PET and postmortem neuropathology.

¹¹C-Pittsburgh compound B (PiB) uptake in PET images is frequently used to analyze β amyloid (Aβ) deposition in living individuals, but its correlation with histologically determined Aβ has not been examined. Six individuals with dementia underwent PiB-PET imaging, and their brains were analyzed neuropathologically (mean interval between imaging and death: 816 days; PiB positive:negative, 3:3; male:female, 3:3; mean age: 84.0 years). PiB uptake (reported as standardized uptake value ratio [SUVR]) was analyzed in 11 cortical regions and 10 subcortical grey matter areas and compared with the Aβ load (% area [the percentage of total area positive for Aβ] and number of neuritic plaques) seen with immunohistochemical staining with an anti-Aβ 11-28 antibody. Two PiB-positive subjects had abundant neuritic plaques and were diagnosed with Alzheimer’s disease (AD). SUVR and % area were strongly correlated in the cortical regions of these subjects (subject 1: r = 0.65, p = 0.03; subject 2: r = 0.80, p = 0.003). The other PiBpositive subject (subject 3) showed focal PiB uptake. In subject 3 and the 3 PiB-negative subjects (subjects 4-6), there was no correlation between regional SUVR and % area or neuritic plaques. PiB uptake was not correlated with Aβ deposition in subcortical regions. High PiB positivity in the cerebral cortex suggests the presence of substantial Aβ deposition and neuritic plaques associated with the pathologic changes of AD. Our results suggest that high cortical SUVR is a reliable marker of AD. Subcortical PiB positivity must be interpreted more carefully

High sensitivity of asymmetric 18F-THK5351 PET abnormality in patients with corticobasal syndrome

Abstract Corticobasal syndrome (CBS) is characterized by symptoms related to the asymmetric involvement of the cerebral cortex and basal ganglia. However, early detection of asymmetric imaging abnormalities can be challenging. Previous studies reported asymmetric 18F-THK5351 PET abnormalities in CBS patients, but the sensitivity for detecting such abnormalities in larger patient samples, including early-stage cases, remains unclear. Patients clinically diagnosed with CBS were recruited. All patients displayed asymmetric symptoms in the cerebral cortex and basal ganglia. Asymmetric THK5351 PET abnormalities were determined through visual assessment. Brain MRI, perfusion SPECT, and dopamine transporter (DAT) SPECT results were retrospectively reviewed. The 15 patients had a median age of 72 years (59–86 years) and a disease duration of 2 years (0.5–7 years). Four patients met the probable and 11 met the possible CBS criteria according to Armstrong criteria at the time of PET examination. All patients, including early-stage cases, exhibited asymmetric tracer uptake contralateral to their symptom-dominant side in the cerebral cortex/subcortical white matter and striatum (100%). The sensitivity for detecting asymmetric imaging abnormalities contralateral to the symptom-dominant side was 86.7% for brain MRI, 81.8% for perfusion SPECT, and 90% for DAT SPECT. White matter volume reduction was observed in the subcortical region of the precentral gyrus with increased THK5351 uptake, occurring significantly more frequently than gray matter volume reduction. THK5351 PET may be a sensitive imaging technique for detecting asymmetric CBS pathologies, including those in early stages

Homovanillic acid and 5-hydroxyindole acetic acid as biomarkers for dementia with Lewy bodies and coincident Alzheimer’s disease: An autopsy-confirmed study

<div><p>Dementia with Lewy bodies (DLB) and Alzheimer’s disease (AD) are the two most common causes of dementia. Both pathologies often coexist, and AD patients with concomitant neocortical LB pathology (referred to as the Lewy body variant of AD) generally show faster cognitive decline and accelerated mortality relative to patients with pure AD. Thus, discriminating among patients with DLB, AD, and coincident DLB and AD is important in clinical practice. We examined levels of homovanillic acid (HVA), 5-hydroxyindole acetic acid (5-HIAA), tau, phosphorylated tau (p-tau), and beta-amyloid (Aβ) 1–42 in cerebrospinal fluid (CSF) to evaluate their viability as biomarkers to discriminate among different forms of dementia. We obtained a total of 3498 CSF samples from patients admitted to our hospital during the period from 1996 to 2015. Of these patients, we were able to carry out a brain autopsy in 94 cases. Finally, 78 neuropathologically diagnosed cases (10 AD, six DLB, five DLB with AD, five controls without neurological diseases, and 52 cases with other neurological diseases) were studied. CSF levels of HVA and 5-HIAA were consistently decreased in pathologically advanced Lewy body disorder (LBD; Braak LB stages >3) compared with pathologically incipient LBD (Braak LB stages <2). These results suggest that if an individual has LB pathology in the central nervous system, CSF levels of HVA and 5-HIAA may decrease after the onset of clinical symptoms. In addition, CSF levels of HVA and 5-HIAA decreased with LB pathology, and were especially low in cases of DLB and DLB with AD. Furthermore, the combination of HVA, 5-HIAA, and brain specific proteins t-tau, p-tau, and Aβ 1–42 in CSF were useful for discriminating among DLB, DLB with AD, and AD with high diagnostic accuracy.</p></div

CSF levels of homovanillic acid (HVA) and 5-hydroxyindole acetic acid (5-HIAA).

<p>5-HIAA levels in the pathologically advanced Lewy body disorder (LBD) group (Braak LB stages ≥3) decreased significantly compared with those in the pathologically incipient LBD groups (Braak LB stages ≤2), as assessed with Student’s <i>t</i> test. Error bars represent the standard deviations and the bottom, middle, and top lines of the box represent the 25th, 50th (median), and 75th percentiles, respectively. *, <i>p</i> < .05.</p

Characteristics of the diagnostic groups.

<p>Characteristics of the diagnostic groups.</p