Overlapping cerebrospinal fluid biomarkers (CSF) levels between Alzheimer's disease (AD) and non-AD patients decrease differential diagnostic accuracy of the AD core CSF biomarkers. Amyloid-β (Aβ) ...isoforms might improve the AD versus non-AD differential diagnosis.
To determine the added diagnostic value of Aβ isoforms, Aβ(1-37), Aβ(1-38), and Aβ(1-40), as compared to the AD CSF biomarkers Aβ(1-42), T-tau, and P-tau(181P).
CSF from patients with dementia due to AD (n = 50), non-AD dementias (n = 50), mild cognitive impairment due to AD (n = 50) and non-demented controls (n = 50) was analyzed with a prototype multiplex assay using MSD detection technology. The non-AD group consisted of frontotemporal dementia (FTD; n = 17), dementia with Lewy bodies (DLB; n = 17), and vascular dementia (n = 16).
Aβ(1-37) and Aβ(1-38) increased accuracy to differentiate AD from FTD or DLB. Aβ(1-37), Aβ(1-38), and Aβ(1-40) levels correlated with Mini-Mental State Examination scores and disease duration in dementia due to AD. The Aβ(1-42)/Aβ(1-40) ratio improved diagnostic performance of Aβ(1-42) in most differential diagnostic situations. Aβ(1-42) levels were lower in APOE ε4 carriers compared to non-carriers.
Aβ isoforms help to differentiate AD from FTD and DLB. Aβ isoforms increase diagnostic performance of Aβ(1-42). In contrast to Aβ1-42, Aβ isoforms seem to be correlated with disease severity in AD. Adding the Aβ isoforms to the current biomarker panel could enhance diagnostic accuracy.
Abstract Background The Target Product Profile (TPP) is a tool used in industry to guide development strategies by addressing user needs and fostering effective communication among stakeholders. ...However, they are not frequently used in academic research, where they may be equally useful. This systematic review aims to extract the features of accessible TPPs, to identify commonalities and facilitate their integration in academic research methodology. Methods We searched peer-reviewed papers published in English developing TPPs for different products and health conditions in four biomedical databases. Interrater agreement, computed on random abstract and paper sets (Cohen’s Kappa; percentage agreement with zero tolerance) was > 0.91. We interviewed experts from industry contexts to gain insight on the process of TPP development, and extracted general and specific features on TPP use and structure. Results 138 papers were eligible for data extraction. Of them, 92% ( n = 128) developed a new TPP, with 41.3% ( n = 57) focusing on therapeutics. The addressed disease categories were diverse; the largest (47.1%, n = 65) was infectious diseases. Only one TPP was identified for several fields, including global priorities like dementia. Our analyses found that 56.5% of papers ( n = 78) was authored by academics, and 57.8% of TPPs ( n = 80) featured one threshold level of product performance. The number of TPP features varied widely across and within product types ( n = 3–44). Common features included purpose/context of use, shelf life for drug stability and validation aspects. Most papers did not describe the methods used to develop the TPP. We identified aspects to be taken into account to build and report TPPs, as a starting point for more focused initiatives guiding use by academics. Discussion TPPs are used in academic research mostly for infectious diseases and have heterogeneous features. Our extraction of key features and common structures helps to understand the tool and widen its use in academia. This is of particular relevance for areas of notable unmet needs, like dementia. Collaboration between stakeholders is key for innovation. Tools to streamline communication such as TPPs would support the development of products and services in academia as well as industry.
•Mavoglurant binds to same allosteric site on mGluR5 as the radioligand 11C-ABP688.•Mavoglurant penetrates brain and induces mGluR5 receptors occupancy in dose- and exposure-dependent manner.•Maximum ...concentrations of mavoglurant were observed around 2–3.25 h post-dose.•A single dose of 400 mg causes 85% receptor occupancy after 3–4 h of administration.
Mavoglurant binds to same allosteric site on metabotropic glutamate receptor 5 (mGluR5) as 11C-ABP688, a radioligand. This open-label, single-center pilot study estimates extent of occupancy of mGluR5 receptors following single oral doses of mavoglurant, using 11C-ABP688 positron emission tomography (PET) imaging, in six healthy males aged 20–40 years. This study comprised three periods and six subjects were divided into two cohorts. On Day 1 (Period 1), baseline clinical data and safety samples were obtained along with PET scan. During Period 2 (1–7 days after Period 1), cohort 1 and 2 received mavoglurant 25 mg and 100 mg, respectively. During Period 3 (7 days after Period 2), cohort 1 and 2 received mavoglurant 200 mg and 400 mg, respectively. Mavoglurant showed the highest distribution volumes in the cingulate region with lower uptake in cerebellum and white matter, possibly because myelinated axonal sheets maybe devoid of mGlu5 receptors. Maximum concentrations of mavoglurant were observed around 2–3.25 h post-dose. Mavoglurant passed the blood–brain barrier and induced dose- and exposure-dependent displacement of 11C-ABP688 from the mGluR5 receptors, 3–4 h post-administration (27%, 59%, 74%, 85% receptor occupancy for mavoglurant 25 mg, 100 mg, 200 mg, 400 mg dose, respectively). There were no severe adverse effects or clinically significant changes in safety parameters.
This is the first human receptor occupancy study completed with Mavoglurant. It served to guide the dosing of mavoglurant in the past and currently ongoing clinical studies. Furthermore, it confirms the utility of 11C-ABP688 as a unique tool to study drug-induced occupancy of mGlu5 receptors in the living human brain.
In this multicenter, double-blind, placebo-controlled, randomized, four way cross-over proof-of-mechanism study, we tested the effect of the positive allosteric α7 nicotinic acetylcholine receptor ...(nAChR) modulator JNJ-39393406 in a key translational assay (sensory P50 gating) in 39 regularly smoking male patients with schizophrenia. All patients were clinically stable and JNJ-39393406 was administered as an adjunct treatment to antipsychotics. No indication was found that JNJ-39393406 has the potential to reverse basic deficits of information processing in schizophrenia (sensory P50 gating) or has a significant effect on other tested electrophysiological markers (MMN, P300 and quantitative resting EEG). Sensitivity analyses including severity of disease, baseline P50 gating, medication and gene variants of the CHRNA7 gene did not reveal any subgroups with consistent significant effects. It is discussed that potential positive effects in subgroups not present or not large enough in the current study or upon chronic dosing are possible, but unlikely to be developed.
This article is part of a Special Issue entitled ‘Cognitive Enhancers’.
► We tested a novel positive allosteric α7 nicotinic acetylcholine receptor modulator. ► Proof-of-mechanism study measuring event-related potentials in stable schizophrenia. ► Multiple dose scheme. ► Sensitivity analyses included gene variants of the CHRNA7 gene. ► No significant drug effect on sensory P50 gating.
To test whether antibodies against β-amyloid are effective in slowing progression of Alzheimer's disease, we assessed cognitive functions in 30 patients who received a prime and a booster ...immunization of aggregated Aβ
42 over a 1 year period in a placebo-controlled, randomized trial. Twenty patients generated antibodies against β-amyloid, as determined by tissue amyloid plaque immunoreactivity assay. Patients who generated such antibodies showed significantly slower rates of decline of cognitive functions and activities of daily living, as indicated by the Mini Mental State Examination, the Disability Assessment for Dementia, and the Visual Paired Associates Test of delayed recall from the Wechsler Memory Scale, as compared to patients without such antibodies. These beneficial clinical effects were also present in two of three patients who had experienced transient episodes of immunization-related aseptic meningoencephalitis. Our results establish that antibodies against β-amyloid plaques can slow cognitive decline in patients with Alzheimer's disease.
Leading Eigenvector Dynamics Analysis (LEiDA) is an analytic approach that characterizes brain activity recorded with functional Magnetic Resonance Imaging (fMRI) as a succession of discrete ...phase-locking patterns, or states, that consistently recur over time across all participants. LEiDA allows for the extraction of three state-related measures which have previously been key to gaining a better understanding of brain dynamics in both healthy and clinical populations: the probability of occurrence of a given state, its lifetime and the probability of switching from one state to another. The degree to which test-retest reliability of the LEiDA measures may be affected by increasing MRI multiband (MB) factors in comparison with single band sequences is yet to be established. In this study, 24 healthy older adults were scanned over three sessions, on weeks 0, 1, and 4. On each visit, they underwent a conventional single band resting-state fMRI (rs-fMRI) scan and three different MB rs-fMRI scans, with MB factors of 4, with and without in-plane acceleration, and 6 without in-plane acceleration. We found test-retest reliability scores to be significantly higher with MB factor 4 with and without in-plane acceleration for most cortical networks. These findings will inform the choice of acquisition parameters for future studies and clinical trials.
Familial Alzheimer’s Disease (FAD) caused by Presenilin-1 (PS1) mutations is characterized by early onset, cognitive impairment and dementia. Impaired gamma secretase function favors production of ...longer beta-amyloid species in PS1 FAD. The PS1 E280A mutation is the largest FAD kindred under study. Here, we studied beta-amyloid deposits in PS1 E280A FAD brains in comparison to sporadic Alzheimer’s disease (SAD). We analyzed cortices and cerebellum from 10 FAD and 10 SAD brains using immunohistochemistry to determine total beta-amyloid, hyperphosphorylated tau (pTau) and specific beta-amyloid peptides 1-38, 1-40, 1-42 and 1-43. Additionally, we studied beta-amyloid subspecies by ELISA, and vessel pathology detected with beta-amyloid 1-42 and truncated pyroglutamylated beta-amyloid antibodies. There were no significant differences in total beta-amyloid signal between SAD and FAD. Beta-amyloid 1-38 and 1-43 loads were increased and 1-42 loads were decreased in frontal cortices of SAD when compared to FAD. Beta-amyloid species assessment by ELISA resembled our findings by immunohistochemical analysis. Differences in beta-amyloid 1-38 and 1-42 levels between SAD and FAD were evidenced by using beta-amyloid length-specific antibodies, reflecting a gamma secretase-dependent shift in beta-amyloid processing in FAD cases. The use of beta-amyloid length-specific antibodies for post-mortem assessment of beta-amyloid pathology can differentiate between SAD and PS1 FAD cases and it can be useful for identification of SAD cases potentially affected with gamma secretase dysfunction.
•In older healthy subjects, FA and MD show overall good test-retest reliability & reproducibility.•MD is sistematically more reproducible than FA across the entire brain anatomy.•FA is more reliable ...than MD in subcortical white matter regions.•In high reliability & low reproducibility regions, variability between subjects is high and statistical power is low.•In low reliability & high reproducibility regions, variability between subjects is low and statistical power is high.
The search for disease-modifying treatments for Parkinson's disease advances, however necessary markers for early detection of the disease are still lacking. There is compelling evidence that changes ...of postural stability occur at very early clinical stages of Parkinson's disease, making it tempting to speculate that changes in sway performance may even occur at a prodromal stage, and may have the potential to serve as a prodromal marker for the disease.
Balance performance was tested in 20 individuals with an increased risk of Parkinson's disease, 12 Parkinson's disease patients and 14 controls using a cross-sectional approach. All individuals were 50 years or older. Investigated groups were similar with respect to age, gender, and height. An accelerometer at the centre of mass at the lower spine quantified sway during quiet semitandem stance with eyes open and closed, as well as with and without foam. With increasing task difficulty, individuals with an increased risk of Parkinson's disease showed an increased variability of trunk acceleration and a decrease of smoothness of sway, compared to both other groups. These differences reached significance in the most challenging condition, i.e. the eyes closed with foam condition.
Individuals with an increased risk of Parkinson's disease have subtle signs of a balance deficit under most challenging conditions. This preliminary finding should motivate further studies on sway performance in individuals with an increased risk of Parkinson's disease, to evaluate the potential of this symptom to serve as a biological marker for prodromal Parkinson's disease.
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