Abstract: Disclosed is a method of inducing or modeling a disease associated with pathological tau protein aggregation. The method can be carried out in vitro and animal models, and may be used to screen for therapeutic, prognostic or diagnostic agents.

Abstract: Disclosed are methods for determining the stage of neurofibrillary degeneration associated with a tauopathy in a subject believed to suffer from the disease, which methods comprise the steps of: (i) introducing into the subject a ligand capable of labelling aggregated paired helical filament (PHF) tau protein, (ii) determining the presence and\or amount of ligand bound to extracellular aggregated PHF tau in the medial temporal lobe of the brain of the subject, (iii) correlating the result of the determination made in (ii) with the extent of neurofibrillary degeneration in the subject. The methods can be used for pre-mortem diagnosis and staging of tauopathies such as Alzheimer's Disease. Preferred ligands include sulphonated-benzothiazole-like compounds and diaminophenothiazines. Novel ligands (e.g. sulphonated-benzothiazole-like compounds) are also provided. The method may also include the use of “blocking ligands” to block competing binding sites.

Abstract: A method for determining the Braak stage of neurofibrillary degeneration associated with a tauopathy in a subject having neurofibrillary degeneration is disclosed. The method comprises the steps of (i) administering to the subject a conjugated, chelated or detectable chemical group-associated ligand that labels aggregated paired helical filament (PHF) tau protein and is capable of crossing the blood brain barrier; (ii) determining the presence and\or amount of ligand bound to extracellular aggregated PHF tau in the medial temporal lobe of the brain of the subject, and (iii) correlating the result of the determination made in (ii) with the extent of neurofibrillary degeneration in the subject. Preferred ligands include sulphonated-benzothiazole-like compounds and diamonophenothiazines.

Abstract: Provided are napthoquinone-type compounds which can be used to modulate the aggregation of protein (e.g. tau) associated with neurodegenerative disease (e.g. Alzheimer's disease). Structure-function characteristics for oxidised and reduced napthoquinone-type compounds, such as menadione-related compounds, are disclosed. The invention further provides methods of treatment or prophylaxis of neurodegenerative diseases and/or clinical dementias based on the compounds.

Abstract: The invention relates generally to the use of diaminophenothiazine compounds to inhibit or reverse the aggregation of synuclein, and for their use in the manufacture of medicaments for this purpose (e.g. for the treatment of Parkinson's Disease). Also provided are related methods of detecting or labelling of aggregated synuclein.

Abstract: The present invention relates to methods for the detection of substances capable of modulating or inhibiting pathological tau-tau protein association. The methods of the present invention are particularly useful in screening substances for the prophylaxis and treatment of Alzheimer's disease.

Abstract: The present invention is directed to methods for the treatment or prophylaxis of a tauopathy comprising administering to a patient in need thereof a medicament comprising a phenothiazine.

Abstract: This invention pertains generally to the field of phenothiazine compounds, and more particularly to certain stably reduced phenothiazine compounds, specifically, certain 3,7 diamino-10H-phenothiazine (DAPTZ) compounds of the following formula wherein: each of R1 and R9 is independently selected from: —H; C1-4alkyl; C2-4alkenyl; and halogenated C1-4alkyl; each of R3NA and R3NB is independently selected from: —H; C1-4alkyl; C2-4alkenyl; and halogenated C1-4alkyl; each of R7NA and R7NB is independently selected from: —H; C1-4alkyl; C2-4alkenyl; and halogenated C1-4alkyl; each of HX1 and HX2 is independently a protic acid; and pharmaceutically acceptable salts, solvates, and hydrates thereof. These compounds are useful as drugs, for example, in the treatment of tauopathies, such as Alzheimer's disease, and also as prodrugs for the corresponding oxidized thioninium drugs (for example, methythioninium chloride, MTC).

Abstract: A method for determining the Braak stage of neurofibrillary degeneration associated with a tauopathy in a subject having neurofibrillary degeneration is disclosed. The method comprises the steps of (i) administering to the subject a conjugated, chelated or detectable chemical group-associated ligand that labels aggregated paired helical filament (PHF) tau protein and is capable of crossing the blood brain barrier; (ii) determining the presence and\or amount of ligand bound to extracellular aggregated PHF tau in the medial temporal lobe of the brain of the subject, and (iii) correlating the result of the determination made in (ii) with the extent of neurofibrillary degeneration in the subject. Preferred ligands include sulphonated-benzothiazole-like compounds and diamonophenothiazines.

Abstract: The present invention relates to methods for the detection of substances capable of modulating or inhibiting pathological tau-tau protein association. The methods of the present invention are particularly useful in screening substances for the prophylaxis and treatment of Alzheiemer's disease.

Abstract: The present invention provides methods of proteolytically converting a precursor protein (e.g. tau) to a product fragment (e.g., a 12 kd fragment) in a stable cell line, wherein the precursor protein is associated with a disease state in which the precursor protein aggregates pathologically (e.g. a tauopathy), and the methods comprise: (a) providing a stable cell line transfected with nucleic acid encoding: (i) a template fragment of the precursor protein such that the template fragment is constitutively expressed in the cell at a level which is not toxic to the cell; and (ii) the precursor protein, which protein is inducibly expressed in the cell in response to a stimulus, whereby interaction of the template fragment with the precursor protein causes a conformational change in the precursor protein such as to cause aggregation and proteolytic processing of the precursor protein to the product fragment.

Abstract: Disclosed are methods for determining the stage of neurofibrillary degeneration associated with a tauopathy in a subject believed to suffer from the disease, by (i) introducing into the subject a ligand capable of labeling aggregated paired helical filament (PHF) tau protein, (ii) determining the presence and/or amount of ligand bound to extracellular aggregated PHF tau in the medial temporal lobe of the brain of the subject, (iii) correlating the result of the determination made in (ii) with the extent of neurofibrillary degeneration in the subject. The methods can be used for pre-mortem diagnosis and staging of tauopathies such as Alzheimer's Disease. Preferred ligands include sulphonated-benzothiazole-like compounds and diaminophenothiazines.

Abstract: A composition and use thereof for the prophylaxis or treatment of Alzheimer's disease, motor neurone disease, Lewy body disease, Pick's disease or progressive supranuclear palsy. The composition includes an agent which modulates or inhibits tau-tau association and which does not inhibit tau-tubulin binding. In the method the agent is administered to an individual in order to achieve the desired therapeutic effect. Preferably the agent which is administered is a phenothiazine compound.

Abstract: An apparatus and method for determining an approximation to a measure of the volatility of fuel on-board a vehicle having an internal combustion engine. The method includes the steps of measuring at least one characteristic of the fuel corresponding to a temperature of the fuel, a volume of the fuel, and a concentration of oxygenates within the fuel; determining an approximation of the a measure of the volatility of the sample volume of fuel using a linear function based on the at least one measured characteristic of the fuel corresponding to temperature, volume, and concentration of oxygenates of the fuel. Preferably, at least one temperature measurement is associated with a predetermined volume of the sample as the sample is evaluated. The method can include determining whether a fuel contains ethanol, and if not, whether the fuel is a winter blend of fuel or a summer blend of fuel.

Abstract: Disclosed are methods for determining the stage of neurofibrillary degeneration associated with a tauopathy in a subject believed to suffer from the disease, by (i) introducing into the subject a ligand capable of labeling aggregated paired helical filament (PHF) tau protein, (ii) determining the presence and/or amount of ligand bound to extracellular aggregated PHF tau in the medial temporal lobe of the brain of the subject, (iii) correlating the result of the determination made in (ii) with the extent of neurofibrillary degeneration in the subject. The methods can be used for pre-mortem diagnosis and staging of tauopathies such as Alzheimer's Disease. Preferred ligands include sulphonated-benzothiazole-like compounds and diaminophenothiazines.

Abstract: Disclosed are methods of proteolytically converting a precursor protein (e.g. tau) to a product fragment (e.g., a 12 kd fragment) in a stable cell line, wherein the precursor protein is associated with a disease state in which the precursor protein aggregates pathologically (e.g. a tauopathy), and the methods comprise: (a) providing a stable cell line transfected with nucleic acid encoding: (i) a template fragment of the precursor protein such that the template fragment is constitutively expressed in the cell at a level which is not toxic to the cell; and (ii) the precursor protein, which protein is inducibly expressed in the cell in response to a stimulus, whereby interaction of the template fragment with the precursor protein causes a conformational change in the precursor protein such as to cause aggregation and proteolytic processing of the precursor protein to the product fragment.

Abstract: An apparatus and method for determining an approximation to a measure of the volatility of fuel on-board a vehicle having an internal combustion engine. The method includes the steps of measuring at least one characteristic of the fuel corresponding to a temperature of the fuel, a volume of the fuel, and a concentration of oxygenates within the fuel; determining an approximation of the a measure of the volatility of the sample volume of fuel using a linear function based on the at least one measured characteristic of the fuel corresponding to temperature, volume, and concentration of oxygenates of the fuel. Preferably, at least one temperature measurement is associated with a predetermined volume of the sample as the sample is evaluated. The method can include determining whether a fuel contains ethanol, and if not, whether the fuel is a winter blend of fuel or a summer blend of fuel.

Abstract: The invention provides an improvement over conventional engine controls by directly measuring fuel volatility, and using this measured value to adjust the engine air/fuel ratio during engine start and initial operation. Engine startability and initial operation are improved as compared to conventional engine control systems by compensating the engine air/fuel ratio during engine start and initial engine operation, using a direct measurement of the fuel volatility.

Abstract: A method of reducing engine cold start up emissions and an apparatus for isolating a fuel sample for testing purposes. According to the methodology the driveability index of the fuel is sensed utilizing an onboard sensor and the sensed fuel driveability index is inputted to the engine controller for utilization by the engine controller in determining the fueling algorithm for minimizing emissions during the next cold start up of the engine. The sensor determines the driveability index by evaluating a fuel sample collected onboard during the previous running cycle of the engine. The fuel sample is pumped from the vehicle fuel tank to an onboard collection point by the vehicle fuel pump during the previous running cycle of the engine. The fuel sampling apparatus includes a sample cup, a cylinder having a bore and an inlet port for connection to the fuel pump and a piston rod defining an axial passage having an inlet port and a discharge port.

Abstract: A method and apparatus for determining a volatility of a fuel sample. A fuel sample is collected in a container and heated for a time period using a heater device. Periodically during the heating, the capacitance of the fuel sample and the temperature of the heater device are determined. After a time period passes, the volatility of the fuel sample is determined using the capacitance decrease and the temperature increase. Specifically, a voltage across the heater device is used, along with the current through the heater device to determine the resistance of the heater device, which gives the temperature of the heater device and the sample. The capacitance and temperature are compared to values derived from experimentation for fuels of varying DI. The first measurement of capacitance with a known sample volume can be used to determine the MTBE or ethanol content in gasoline fuels.