Electrophoretics Limited

Other

King's College London

Proteome Sciences Plc

Medical Research Council

University College London

Medical Research Council Technology

Malcolm Andrew Ward

Helen Louise Byers

Ian Hugo Pike

James Campbell

Nicola Louise Leeds

Emma McGregor

Simon Lovestone

Brian H Anderton

Christian Baumann

Claire Louise Russell

Jules Arthur Westbrook

Jules Westbrook

Abdul Hye

John Collinge

Karsten Kuhn

Peter Schulz-Knappe

Stefan Kienle

Graham Stuart Jackson

Richard Joubert

Juergen Schaefer

Petra Prefot

Vikram Mitra

Richard James Butler Dobson

Thorsten Prinz

Stephen Lynham

Ritchie Williamson

Pascal Derkinderen

Annette Dalrymple

Sarah Joanna Tabrizi

Darragh Patrick William O'Brien

Kit-Yi Leung

Vaksha Patel

Diane Hanger

Christopher Hugh Reynolds

Brian Henry Anderton

Hui-Chung Liang

Simon Harold Lovestone

Darragh Patrick William O'BRIEN

Richard James Dobson

The invention relates to panels of biomarkers including proteins phosphatase 1 regulatory subunit 14A and/or 2',3′-cyclic-nucleotide 3′-phosphodiesterase and/or phosphorylated tau or fragments thereof and methods using thereof for diagnosing, staging, treating and assessing the response of a treatment for a neurocognitive disorder characterised by tau toxicity, in particular for Alzheimer's disease. The present invention shows that the biomarkers disclosed herein are elevated in the brain of subjects with an advanced stage of a neurocognitive disorder (Braak stage V/VI) and/or are regulated in the CSF of AD subjects in comparison to cognitively affected non-AD controls; and/or regulated in response to two casein kinase 1 delta inhibitors.

Biomolecules involved in Alzheimer's disease

Alzheimer's disease, the most common cause of dementia in older individuals, is a debilitating neurodegenerative disease for which there is currently no cure. In the past, AD could only be definitively diagnosed by brain biopsy or upon autopsy after a patient died. These methods, which demonstrate the presence of the characteristic plaque and tangle lesions in the brain, are still considered the gold standard for the pathological diagnoses of AD. However, in the clinical setting brain biopsy is rarely performed and diagnosis depends on a battery of neurological, psychometric and biochemical tests, including the measurement of biochemical markers such as the ApoE and tau proteins or the beta-amyloid peptide in cerebrospinal fluid and blood. The present invention discloses and describes panels of makers that are differentially expressed in the disease state relative to their expression in the normal state and, in particular, identifies and describes panels of makers associated with neurocognitive disorders. Such biomarker panel might have considerable value in triaging patients with early memory disorders to yet more specific but more invasive and costly approaches such as molecular markers in CSF and on PET imaging in clinical trials and possibly in clinical practice.

Biomarkers and methods relating to Alzheimer's disease

Alzheimer's disease (AD) is the most common type of dementia in aging adults with the number of people living with AD projected to increase, making the search for treatments and tools to diagnose and measure disease progression increasingly urgent. In particular, ideal biomarkers for diagnosis of AD should not only have high specificity for disease versus non-disease and high sensitivity for distinguishing between disease types but also should be able to detect changes at a very early stage of the disease. Using microglia activation as an early event of AD's onset, the present inventors have identified a panel of biomarkers in CSF which has the potential to diagnose, stage and determine the likelihood of developing AD.

Materials and methods for diagnosis and treatment of Alzheimer's disease

The disclosure provides a method for assaying for a target analyte, comprising providing a plurality of samples which may comprise the target analyte, wherein each sample is differentially labelled with a mass label or a combination of mass labels, wherein the mass labels are from a set of mass labels, wherein each mass label is an isobaric mass label comprising a mass spectrometrically distinct mass marker group, such that the samples can be distinguished by mass spectrometry and determining from the mass spectrum the quantity of the target analyte in each sample.

Mass spectrometric analysis

The invention relates to a method of diagnosis of vCJD in a diagnostic sample of a valid body tissue taken from a human subject, which comprises detecting an increased concentration of a protein in the diagnostic sample, compared with a sample of a control human subject, the protein being: beta-actin (SwissProt Acc. No. P60709), apolipoprotein A-IV precursor (SwissProt Acc. No. P06727); haptoglobin beta-chain consisting of residues 162-406 (SwissProt Acc. No. P00738); haemoglobin beta chain (SwissProt Acc. No. P02023); or alpha-1-antitrypsin (SwissProt Acc. No. P01009); or a decreased concentration of a protein in the diagnostic sample, compared with a sample of a control, normal human subject, the protein being plasma protease (C1) inhibitor precursor (SwissProt Acc. No. P05155); complement component 1, s sub-component (SwissProt Acc. No. P09871); butyrylcholinesterase precursor (SwissProt Acc. No. P06276); complement component C4B (SwissProt Acc. No. P01028); lumican (SwissProt Acc. No. P51884); alpha-fibrinogen precursor (SwissProt Acc. No. P02671); IGHG4 protein (Swiss Prot Acc. No. Q8TC63) or immunoglobulin lambda heavy chain. Other marker proteins are also disclosed.

Diagnosis of neurodegenerative diseases

Methods for screening for substances capable of modulating the phosphorylation of tau protein are disclosed, and in particular paired helical filament (PHF) tau, and the use of such modulators in the treatment of tauopathies. The assays and screening methods are based on the identification of new phosphorylation sites in PHF tau and new kinases and combinations of kinases as therapeutic targets, in particular the identification of casein kinase 1 as a kinase which phosphorylates tau protein.

Methods for screening for inhibitors of tau phosphorylation by casein kinase I

Methods and compositions relating to Alzheimer's disease are provided, including proteins that are differentially expressed in Alzheimer's disease as compared to the normal state. Further provided are methods, particularly experimental paradigms, for the identification of differential expressed proteins that are potential molecular targets for compounds to treat or prevent Alzheimer's disease. Also provided are methods for the identification and therapeutic use of compounds for the prevention and treatment of Alzheimer's disease.

Methods and compositions relating to alzheimer's disease

The invention provides a method of diagnosis of a spongiform encephalopathy in a diagnostic sample of a valid body tissue taken from a subject, which comprises detecting an increased proteolytic activity in the diagnostic sample, compared with a sample from a control subject.

Diagnostic assay for spongiform encephalopathies

The invention relates to a method of diagnosis of Huntington's Disease in a diagnostic sample of a valid body tissue taken from a human subject, which comprises detecting an altered concentration of a protein in the diagnostic sample, compared with a sample of a control human subject, the protein being selected from: Swiss Prot accession number: Protein name; P10909: Clusterin precursor; P00738: Haptoglobin precursor; P01009: Alpha-1-antitrypsin precursor; P01024: Complement C3 precursor; P01620: 1g kappa chain V-III region; P01834: 1 g kappa chain C region P01842: 1g lambda chain C regions; P01857: 1g gamma-1 chain C region; P01859: Ig gamma-2 chain C region; P01876: 1g alpha-1 chain C region P02647: Apolipoprotein A-I precursor; P02649: Apolipoprotein E precursor; P02652: Apolipoprotein A-II precursor; P02655: Apolipoprotein C-II precursor; P02656: Apolipoprotein C-II precursor P02671: Fibrinogen alpha/alpha-E chain precursor; P02763: Alpha-1-acid glycoprotein 1 precursor; P02766: Transthyretin precursor; P02768: Serum albumin precursor; P02787: Serotransferrin precursor; P04196: Histidine-rich glycoprotein precursor; P06727: Apolipoprotein A-IV precursor; P19652: Alpha-1-acid glycoprotein 2 precursor; P68871/P02042: Hemoglobin beta chain/Hemoglobin delta chain; P60709: Beta actin.

Methods and compositions for monitoring progression of huntington's disease

The present invention provides methods of screening for candidate compounds useful in the treatment of Alzheimer's disease and related conditions by inhibiting specific phosphorylation of tau protein by tyrosine kinase c-Abl.

Method of screening for inhibitors of tau protein phosphororylation by tyrosine kinase c-Abl

Methods and compositions relating to Alzheimer's disease are provided. Specifically, proteins that are differentially expressed in the Alzheimer's disease state relative to their expression in the normal state are provided. Proteins associated with Alzheimer's disease are identified and described. Methods of diagnosis of Alzheimer's disease using the differentially expressed proteins are also provided, as are methods for the identification and therapeutic use of compounds for the prevention and treatment of Alzheimer's disease.

Methods of diagnosing Alzheimer's disease

Growing community of inventors

Shefford, United Kingdom

Malcolm Andrew Ward