Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving antigen-antibody binding – specific binding protein...
Reexamination Certificate
2001-06-27
2003-12-30
Ulm, John (Department: 1646)
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving antigen-antibody binding, specific binding protein...
C435S007210, C435S007800, C436S501000, C530S350000, C530S300000, C530S387100
Reexamination Certificate
active
06670137
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to the field of the diagnosis of neurological diseases. The present invention provides a new method for the differential diagnosis of Alzheimer's disease versus other neurological diseases. More particular, the present invention provides a method for the differential diagnosis of Alzheimer's disease versus dementia with Lewy bodies, versus Parkinson's disease without dementia, versus multi-system atrophy and/or versus progressive supranuclear palsy.
BACKGROUND OF THE INVENTION
The use of tau and phospho-tau as neurological markers in the diagnosis of neurological diseases has been postulated (Blennow et al., 1995; Vigo-Pelfrey et al., 1995; Andreasen et al., 1998; Andreasen et al., 1999a; Ishiguro et al., 1999). The microtubule-associated protein tau is a major protein component of paired helical filaments (PHF) and neurofibrillar tangles (NFT), associated with Alzheimer's disease (Brion et al., 1985; Delacourte and Defossez, 1986; Grundke-Iqbal et al., 1986; Kosik et al., 1986; Wood et al., 1986; Kondo et al., 1988). Tau protein exists in different isoforms, of which 4 to 6 are found in adult brain but only 1 isoform is detected in fetal brain. The diversity of the isoforms is generated from a single gene on human chromosome 17 by alternative mRNA splicing (Himmler, 1989; Goedert et al., 1989; Andreadis et al., 1992). The most striking feature of tau protein, as deduced from molecular cloning, is a stretch of 31 or 32 amino acids, occurring in the carboxy-terminal part of the molecule, which can be repeated either 3 or 4 times. Additional diversity is generated through 29 or 58 amino acid-long insertions in the NH
2
-terminal part of tau molecules (Goedert et al., 1989). In vivo tau promotes microtubule assembly and stability in the axonal compartment of neurons by interactions involving its microtubule binding domain which is localized in the repeat region of tau (255-381) (Lewis et al., 1988). In normal circumstances adult brain contains 2-3 mole phosphate per mole of tau (Selden and Pollard, 1983; Ksiezak-Reding et al., 1992). Phosphorylation of different sites in normal tau as studied in rat and humans is dependent on the developmental state (Lee et al., 1991; Bramblett et al., 1993; Goedert et al., 1993). Tau variants of 60, 64 and 68 kDa arising as a consequence of phosphorylation have been detected in brain areas showing neurofibrillary tangles (Delacourte et al., 1990; Goedert et al., 1992; Flament et al., 1990, Greenberg and Davies, 1990). These brains contain 6-8 mole phosphate per mole tau (Ksiezak-Reding et al., 1992). In tau isolated from PHF (PHF-tau), phosphorylation occurs at several positions (Iqbal et al., 1989; Lee et al., 1991; Hasegawa et al., 1992; Hanger et al., 1998; Buee et al., 1999).
Alzheimer's disease (AD) and frontotemporal dementia (FTD) are the most common types of primary degenerative dementia associated with a tau pathology, having a prevalence of respectively 42-75% and 8-10% (Brun, 1993; Gustafson, 1993; Ebly et al., 1994). Filamentous tau pathology i.e. neurofibrillary tangles (NFT), are consistently found in AD (Tomlinson and Corsellis, 1984) but may also be found in FTD (Spillantini and Goedert, 1998). Pathological tau proteins are found both in AD and FTD (Vermersch et al., 1995; Delacourte et al., 1996). Studies on brain tissue, however, have suggested that the tau pathology differs between AD and FTD, possibly being related to the degree of phosphorylation (Delacourte et al., 1996). Other forms of dementia associated with a tau pathology include familial FTD, progressive supranuclear palsy (PSP), corticobasal degeneration (CBD) and subacute sclerosing panencephalitis. The role of hyperphosphorylation in the pathology of these tauopathies is at present not well understood.
Dementia with Lewy bodies (DLB) is an illness that presents with progressive dementia or psychosis. Parkinsonian signs, which may be absent or mild at the onset, eventually become common and rigidity is usually severe. Lewy bodies are found profusely in the brainstem, basal forebrain, hypothalamic nuclei and neocortex. Dementia with Lewy bodies is characterized by the relative absence of tangles and hyperphosphorylated tau in the brain. Parkinson's disease (PD) is a type of Lewy Body disease occurring in the middle or late life, with very gradual progression and a prolonged course. It can be considered as an example of neuronal system disease, involving mainly the nigrostriatal dopaminergic system. Dementia with Lewy bodies was recently defined as a special form of dementia requiring differential patient management (Lebert et al., 1998; McKeith et al., 1999). Dementia with Lewy bodies, which is sensitive to neuroleptics, is clinically very difficult to differentiate from Alzheimer's disease (McKeith et al., 1996; Ballard et al., 1998). Most patients (more than 75%) are neuropathologically defined as Alzheimer's disease patients while it is estimated that 15 to 25% of the clinically diagnosed Alzheimer's disease patients have dementia with Lewy bodies (Hooten et al., 1998). As dementia with Lewy bodies is more susceptible to acetylcholinesterase treatment, differentiation of dementia with Lewy bodies from Alzheimer's disease is essential for optimization of treatment (Levy et al., 1994; Perry et al., 1994; Wilcock et al., 1994).
Cerebrospinal fluid (CSF)-&bgr;-amyloid and CSF-tau have been validated to discriminate Alzheimer's disease from normal aging, depression and Parkinson's disease (Galasko et al., 1998; Kanai et al., 1998; Hulstaert et al., 1999) and these markers are well suited for the differential diagnosis of these disorders (Andreasen et al., 1999b). More controversial, however, is their role in the discrimination of Alzheimer's disease from closely related conditions such as dementia with Lewy bodies and from other dementia associated with tau pathology such as frontotemporal dementia, multi-system atrophy (MSA) and/or progressive supranuclear palsy. At present, no accurate methods exist for the differential diagnosis of these neurological diseases.
AIMS OF THE INVENTION
It is an aim of the present invention to provide a method for the differential diagnosis of an individual suffering from Alzheimer's disease versus an individual suffering from another neurological disease.
It is an aim of the present invention to provide a method for the differential diagnosis of an individual suffering from Alzheimer's disease versus an individual suffering from dementia with Lewy bodies.
It is an aim of the present invention to provide a method for the differential diagnosis of an individual suffering from Alzheimer's disease versus an individual suffering from Parkinson's disease without dementia.
It is an aim of the present invention to provide a method for the differential diagnosis of an individual suffering from Alzheimer's disease versus an individual suffering from multi-system atrophy.
It is an aim of the present invention to provide a method for the differential diagnosis of an individual suffering from Alzheimer's disease versus an individual suffering from progressive supranuclear palsy.
It is an aim of the present invention to provide an in vitro method for the differential diagnosis of an individual suffering from Alzheimer's disease versus an individual suffering from another neurological disease.
It is an aim of the present invention to provide an in vitro method for the differential diagnosis of an individual suffering from Alzheimer's disease versus an individual suffering from dementia with Lewy bodies.
It is an aim of the present invention to provide an in vitro method for the differential diagnosis of an individual suffering from Alzheimer's disease versus an individual suffering from Parkinson's disease without dementia.
It is an aim of the present invention to provide an in vitro method for the differential diagnosis of an individual suffering from Alzheimer's disease versus a
Hulstaert Frank
Vanderstichele Hugo
VanMechelen Eugeen
Chernyshev Olga N.
Howrey Simon Arnold & White , LLP
Innogenetics N.V.
Ulm John
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