A preliminary analysis of a trial involving participants with brain amyloid deposition who are at risk for dementia due to Alzheimer’s disease showed no benefit of a β-secretase enzyme inhibitor over ...placebo and a potential signal of worse cognitive test scores over 3 and 6 months.
In two phase 3 placebo-controlled, randomized trials in 1012 and 1040 patients with mild-to-moderate Alzheimer's disease, solanezumab, a humanized monoclonal antibody that preferentially binds ...soluble forms of amyloid, did not improve cognition or functional status.
Alzheimer's disease is associated with the accumulation of aggregated amyloid-beta (Aβ) peptide in the cerebral cortex and hippocampus. One approach to reducing brain amyloid involves increasing the clearance of Aβ by means of prolonged treatment with monoclonal antibodies directed against this peptide. In preclinical studies, a murine antibody that targeted the central domain of Aβ and was selective for soluble forms slowed Aβ deposition in a transgenic mouse model
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; in another transgenic murine model, Aβ–antibody complexes were present in the cerebrospinal fluid (CSF) and plasma, and behavioral deficits were reversed without a decrease in amyloid plaques, as assessed by . . .
In this placebo-controlled trial, the γ-secretase inhibitor semagacestat did not improve cognitive status in patients with Alzheimer's disease and was associated with more adverse events than ...placebo, including skin cancers and infections.
Alzheimer's disease begins decades before the appearance of clinical symptoms, with the deposition of aggregated amyloid-beta (Aβ) peptide plaques in the cortex and hippocampus. This protein is cleaved from the amyloid precursor protein (APP) by the sequential action of β- and γ-secretases, producing fragments that include Aβ1-40 and Aβ1-42. Since the accumulation of aggregated Aβ is associated with disease progression, both β-secretase and γ-secretase represent potential therapeutic targets. Multiple small molecules can inhibit γ-secretase in vitro,
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but Notch and other transmembrane proteins are also substrates for γ-secretase,
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and studies have raised concern that the inhibition of γ-secretase could . . .
Intranasal insulin (INI) has shown promise as a treatment for Alzheimer's disease (AD) in pilot clinical trials. In a recent phase 2 trial, participants with mild cognitive impairment (MCI) or AD who ...were treated with INI with one of two delivery devices showed improved cerebral spinal fluid (CSF) biomarker profiles and slower symptom progression compared with placebo. In the cohort which showed benefit, we measured changes in CSF markers of inflammation, immune function and vascular integrity and assessed their relationship with changes in cognition, brain volume, and CSF amyloid and tau concentrations. The insulin-treated group had increased CSF interferon-γ (p = 0.032) and eotaxin (p = 0.049), and reduced interleukin-6 (p = 0.048) over the 12 month trial compared to placebo. Trends were observed for increased CSF macrophage-derived chemokine for the placebo group (p = 0.083), and increased interleukin-2 in the insulin-treated group (p = 0.093). Insulin-treated and placebo groups showed strikingly different patterns of associations between changes in CSF immune/inflammatory/vascular markers and changes in cognition, brain volume, and amyloid and tau concentrations. In summary, INI treatment altered the typical progression of markers of inflammation and immune function seen in AD, suggesting that INI may promote a compensatory immune response associated with therapeutic benefit.
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Trial of Solanezumab in Preclinical Alzheimer’s Disease Sperling, Reisa A.; Donohue, Michael C.; Raman, Rema ...
New England journal of medicine/The New England journal of medicine,
09/2023, Volume:
389, Issue:
12
Journal Article
Peer reviewed
Open access
In cognitively normal persons with brain amyloid deposition, solanezumab (an antibody targeting monomeric amyloid) did not slow cognitive decline as compared to placebo over a period of 4.5 years.
Introduction
The Alzheimer's disease (AD) continuum begins with a long asymptomatic or preclinical stage, during which amyloid beta (Aβ) is accumulating for more than a decade prior to widespread ...cortical tauopathy, neurodegeneration, and manifestation of clinical symptoms. The AHEAD 3‐45 Study (BAN2401‐G000‐303) is testing whether intervention with lecanemab (BAN2401), a humanized immunoglobulin 1 (IgG1) monoclonal antibody that preferentially targets soluble aggregated Aβ, initiated during this asymptomatic stage can slow biomarker changes and/or cognitive decline. The AHEAD 3‐45 Study is conducted as a Public‐Private Partnership of the Alzheimer's Clinical Trial Consortium (ACTC), funded by the National Institute on Aging, National Institutes of Health (NIH), and Eisai Inc.
Methods
The AHEAD 3‐45 Study was launched on July 14, 2020, and consists of two sister trials (A3 and A45) in cognitively unimpaired (CU) individuals ages 55 to 80 with specific dosing regimens tailored to baseline brain amyloid levels on screening positron emission tomography (PET) scans: intermediate amyloid (≈20 to 40 Centiloids) for A3 and elevated amyloid (>40 Centiloids) for A45. Both trials are being conducted under a single protocol, with a shared screening process and common schedule of assessments. A3 is a Phase 2 trial with PET‐imaging end points, whereas A45 is a Phase 3 trial with a cognitive composite primary end point. The treatment period is 4 years. The study utilizes innovative approaches to enriching the sample with individuals who have elevated brain amyloid. These include recruiting from the Trial‐Ready Cohort for Preclinical and Prodromal Alzheimer's disease (TRC‐PAD), the Australian Dementia Network (ADNeT) Registry, and the Japanese Trial Ready Cohort (J‐TRC), as well as incorporation of plasma screening with the C2N mass spectrometry platform to quantitate the Aβ 42/40 ratio (Aβ 42/40), which has been shown previously to reliably identify cognitively normal participants not likely to have elevated brain amyloid levels. A blood sample collected at a brief first visit is utilized to "screen out" individuals who are less likely to have elevated brain amyloid, and to determine the participant's eligibility to proceed to PET imaging. Eligibility to randomize into the A3 Trial or A45 Trial is based on the screening PET imaging results.
Result
The focus of this article is on the innovative design of the study.
Discussion
The AHEAD 3‐45 Study will test whether with lecanemab (BAN2401) can slow the accumulation of tau and prevent the cognitive decline associated with AD during its preclinical stage. It is specifically targeting both the preclinical and the early preclinical (intermediate amyloid) stages of AD and is the first secondary prevention trial to employ plasma‐based biomarkers to accelerate the screening process and potentially substantially reduce the number of screening PET scans.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Abstract Motivation Diseases that progress slowly are often studied by observing cohorts at different stages of disease for short periods of time. The Alzheimer's Disease Neuroimaging Initiative ...(ADNI) follows elders with various degrees of cognitive impairment, from normal to impaired. The study includes a rich panel of novel cognitive tests, biomarkers, and brain images collected every 6 months for as long as 6 years. The relative timing of the observations with respect to disease pathology is unknown. We propose a general semiparametric model and iterative estimation procedure to estimate simultaneously the pathological timing and long-term growth curves. The resulting estimates of long-term progression are fine-tuned using cognitive trajectories derived from the long-term “Personnes Agées Quid” study. Results We demonstrate with simulations that the method can recover long-term disease trends from short-term observations. The method also estimates temporal ordering of individuals with respect to disease pathology, providing subject-specific prognostic estimates of the time until onset of symptoms. When the method is applied to ADNI data, the estimated growth curves are in general agreement with prevailing theories of the Alzheimer's disease cascade. Other data sets with common outcome measures can be combined using the proposed algorithm. Availability Software to fit the model and reproduce results with the statistical software R is available as the grace package. ADNI data can be downloaded from the Laboratory of NeuroImaging.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Summary Background To increase the effective use of thrombolytics for acute stroke, the expertise of vascular neurologists must be disseminated more widely. We prospectively assessed whether ...telemedicine (real-time, two-way audio and video, and digital imaging and communications in medicine DICOM interpretation) or telephone was superior for decision making in acute telemedicine consultations. Methods From January, 2004, to August, 2007, patients older than 18 years who presented with acute stroke symptoms at one of four remote spoke sites were randomly assigned, through a web-based, permuted blocks system, to telemedicine or telephone consultation to assess their suitability for treatment with thrombolytics, on the basis of standard criteria. The primary outcome measure was whether the decision to give thrombolytic treatment was correct, as determined by central adjudication. Secondary outcomes were the rate of thrombolytic use, 90-day functional outcomes (Barthel index BI and modified Rankin scale mRS), the incidence of intracerebral haemorrhages, and technical observations. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov , number NCT00283868. Findings 234 patients were assessed prospectively. 111 patients were randomised to telemedicine, and 111 patients were randomised to telephone consultation; 207 completed the study. Mean National Institutes of Health stroke scale score at presentation was 9·5 (SD 8·1) points (11·4 8·7 points in the telemedicine group versus 7·7 7·0 points in the telephone group; p=0·002). One telemedicine consultation was aborted for technical reasons, although it was included in the analyses. Correct treatment decisions were made more often in the telemedicine group than in the telephone group (108 98% vs 91 82%, odds ratio OR 10·9, 95% CI 2·7–44·6; p=0·0009). Intravenous thrombolytics were used at an overall rate of 25% (31 28% telemedicine vs 25 23% telephone, 1·3, 0·7–2·5; p=0·43). 90-day functional outcomes were not different for BI (95–100) (0·6, 0·4–1·1; p=0·13) or for mRS score (0·6, 0·3–1·1; p=0·09). There was no difference in mortality (1·6, 0·8–3·4; p=0·27) or rates of intracerebral haemorrhage after treatment with thrombolytics (2 7% telemedicine vs 2 8% telephone, 0·8, 0·1–6·3; p=1·0). However, there were more incomplete data in the telephone group than in the telemedicine group (12% vs 3%, 0·2, 0·1–0·3; p=0·0001). Interpretation The authors of this trial report that stroke telemedicine consultations result in more accurate decision making compared with telephone consultations and can serve as a model for the effectiveness of telemedicine in other medical specialties. The more appropriate decisions, high rates of thrombolysis use, improved data collection, low rate of intracerebral haemorrhage, low technical complications, and favourable time requirements all support the efficacy of telemedicine for making treatment decisions, and might enable more practitioners to use this medium in daily stroke care. Funding National Institute of Neurological Disorders and Stroke; California Institute of Telecommunications Technology; Department of Veterens' Affairs Research Division.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Abstract The Clinical Core of the Alzheimer's Disease Neuroimaging Initiative (ADNI) has provided clinical, operational, and data management support to ADNI since its inception. This article reviews ...the activities and accomplishments of the core in support of ADNI aims. These include the enrollment and follow-up of more than 800 subjects in the three original cohorts: healthy controls, amnestic mild cognitive impairment (now referred to as late MCI, or LMCI), and mild Alzheimer's disease (AD) in the first phase of ADNI (ADNI 1), with baseline longitudinal, clinical, and cognitive assessments. These data, when combined with genetic, neuroimaging, and cerebrospinal fluid measures, have provided important insights into the neurobiology of the AD spectrum. Furthermore, these data have facilitated the development of novel clinical trial designs. ADNI has recently been extended with funding from an NIH Grand Opportunities (GO) award, and the new ADNI GO phase has been launched; this includes the enrollment of a new cohort, called early MCI, with milder episodic memory impairment than the LMCI group. An application for a further 5 years of ADNI funding (ADNI 2) was recently submitted. This funding would support ongoing follow-up of the original ADNI 1 and ADNI GO cohorts, as well as additional recruitment into all categories. The resulting data would provide valuable data on the earliest stages of AD, and support the development of interventions in these critically important populations.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
We identified axonal defects in mouse models of Alzheimer's disease that preceded known disease-related pathology by more than a year; we observed similar axonal defects in the early stages of ...Alzheimer's disease in humans. Axonal defects consisted of swellings that accumulated abnormal amounts of microtubule-associated and molecular motor proteins, organelles, and vesicles. Impairing axonal transport by reducing the dosage of a kinesin molecular motor protein enhanced the frequency of axonal defects and increased amyloid-{szligbeta} peptide levels and amyloid deposition. Reductions in microtubule-dependent transport may stimulate proteolytic processing of {szligbeta}-amyloid precursor protein, resulting in the development of senile plaques and Alzheimer's disease.
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
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