CSF p-Tau levels in the prediction of Alzheimer's disease

Summary The two hallmarks of Alzheimer's disease (AD) are neurofibrillary tangles and amyloid plaques. Neurofibrillary tangles are formed due to the hyperphosphorylation of tau protein. There is an urgent need to develop a reliable biomarker for the diagnosis of AD. Cerebrospinal fluid (CSF) is surrounding the brain and reflects the major neuropathological features in the AD brain. Diagnosis, disease progression and drug actions rely on the AD biomarkers. Mainly CSF tau and phosphorylated tau (p-Tau) have been observed to serve the purpose for early AD. Keeping in view the early appearance of p-Tau in CSF, we analyzed p-Tau levels in 23 AD, 23 Non AD type dementia (NAD), 23 Neurological control (NC) and 23 Healthy control (HC) North Indian patients. The levels of p-Tau were found to be increased in AD patients (67.87±18.05 pg/ml, SEM 3.76) compared with NAD (47.55±7.85 pg/ml, SEM 1.64), NC (34.42±4.51 pg/ml, SEM 0.94) and HC (27.09±7.18 pg/ml, SEM 1.50). The resulting sensitivity for AD with NAD was 80.27% whereas with respect to the NAD, NC and HC was 85.40%. Therefore elevated levels of p-Tau in AD can be exploited as a predictive biomarker in North Indian AD patients.

[1]  K. Herholz,et al.  CSF total and phosphorylated tau protein, regional glucose metabolism and dementia severity in Alzheimer’s disease , 2008, European journal of neurology.

[2]  M. Folstein,et al.  Clinical diagnosis of Alzheimer's disease: Report of the NINCDS—ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer's Disease , 2011, Neurology.

[3]  R. Kandimalla,et al.  siRNA against presenilin 1 (PS1) down regulates amyloid β42 production in IMR-32 cells , 2012, Journal of Biomedical Science.

[4]  K. Blennow,et al.  Tau protein in cerebrospinal fluid: a biochemical marker for axonal degeneration in Alzheimer disease? , 1995, Molecular and chemical neuropathology.

[5]  K. Blennow,et al.  CSF markers for Alzheimer's disease: Total tau, phospho-tau and Aβ42 , 2003, The world journal of biological psychiatry : the official journal of the World Federation of Societies of Biological Psychiatry.

[6]  Katharina Buerger,et al.  Differential diagnosis of Alzheimer disease with cerebrospinal fluid levels of tau protein phosphorylated at threonine 231. , 2002, Archives of neurology.

[7]  Hiroyuki Arai,et al.  Phosphorylated tau in human cerebrospinal fluid is a diagnostic marker for Alzheimer's disease , 1999, Neuroscience Letters.

[8]  M. Folstein,et al.  Clinical diagnosis of Alzheimer's disease , 1984, Neurology.

[9]  E. Sinforiani,et al.  Cerebrospinal fluid levels of tau phosphorylated at threonine 181 in patients with Alzheimer’s disease and vascular dementia , 2008, Neurological Sciences.

[10]  R. Nitsch,et al.  Biochemical diagnosis of Alzheimer disease by measuring the cerebrospinal fluid ratio of phosphorylated tau protein to beta-amyloid peptide42. , 2003, Archives of neurology.

[11]  L. Parnetti,et al.  CSF phosphorylated tau is a possible marker for discriminating Alzheimer's disease from dementia with Lewy bodies , 2001, Neurological Sciences.

[12]  H. Hampel,et al.  Detection of tau phosphorylated at threonine 231 in cerebrospinal fluid of Alzheimer's disease patients , 2000, Neuroscience Letters.

[13]  L. Parnetti,et al.  Cerebrospinal Fluid Biomarkers and Prediction of Conversion in Patients with Mild Cognitive Impairment: 4-Year Follow-Up in a Routine Clinical Setting , 2009, TheScientificWorldJournal.

[14]  K. Blennow,et al.  Decreased CSF-beta-amyloid 42 in Alzheimer's disease and amyotrophic lateral sclerosis may reflect mismetabolism of beta-amyloid induced by disparate mechanisms. , 2002, Dementia and Geriatric Cognitive Disorders.

[15]  Katharina Buerger,et al.  Measurement of phosphorylated tau epitopes in the differential diagnosis of Alzheimer disease: a comparative cerebrospinal fluid study. , 2004, Archives of general psychiatry.

[16]  R. Kandimalla,et al.  Apo-E4 Allele in Conjunction with Aβ42 and Tau in CSF: Biomarker for Alzheimers Disease , 1970 .

[17]  Jan Six,et al.  Detection of Proteins in Normal and Alzheimer's Disease Cerebrospinal Fluid with a Sensitive Sandwich Enzyme‐Linked Immunosorbent Assay , 1993 .

[18]  H. Vanderstichele,et al.  Phospho-tau/total tau ratio in cerebrospinal fluid discriminates Creutzfeldt–Jakob disease from other dementias , 2003, Molecular Psychiatry.

[19]  H. Hampel,et al.  Advances in the development of biomarkers for Alzheimer’s disease: from CSF total tau and Aβ1–42 proteins to phosphorylated tau protein , 2003, Brain Research Bulletin.

[20]  K. Blennow,et al.  Increased levels of CSF phosphorylated tau in apolipoprotein E ɛ4 carriers with mild cognitive impairment , 2005, Neuroscience Letters.

[21]  P. Calabresi,et al.  Performance of aβ1-40, aβ1-42, total tau, and phosphorylated tau as predictors of dementia in a cohort of patients with mild cognitive impairment. , 2012, Journal of Alzheimer's disease : JAD.

[22]  Juan Manuel Maler,et al.  Tau protein phosphorylated at threonine 181 in CSF as a neurochemical biomarker in Alzheimer’s disease , 2007, Journal of Molecular Neuroscience.

[23]  K. Blennow,et al.  Increased levels of CSF phosphorylated tau in apolipoprotein E epsilon4 carriers with mild cognitive impairment. , 2005, Neuroscience letters.

[24]  H. Soininen,et al.  Cerebrospinal fluid {beta}-amyloid 42 and tau proteins as biomarkers of Alzheimer-type pathologic changes in the brain. , 2009, Archives of neurology.

[25]  I. Grundke‐Iqbal,et al.  Levels of nonphosphorylated and phosphorylated tau in cerebrospinal fluid of Alzheimer's disease patients : an ultrasensitive bienzyme-substrate-recycle enzyme-linked immunosorbent assay. , 2002, The American journal of pathology.

[26]  K. Blennow,et al.  Both total and phosphorylated tau are increased in Alzheimer's disease , 2001, Journal of neurology, neurosurgery, and psychiatry.

[27]  K. Blennow,et al.  Decreased CSF-β-Amyloid 42 in Alzheimer’s Disease and Amyotrophic Lateral Sclerosis May Reflect Mismetabolism of β-Amyloid Induced by Disparate Mechanisms , 2002, Dementia and Geriatric Cognitive Disorders.

[28]  J. Trojanowski,et al.  Advances in tau-focused drug discovery for Alzheimer's disease and related tauopathies , 2009, Nature Reviews Drug Discovery.

[29]  P. Scheltens,et al.  Total tau and phosphorylated tau 181 levels in the cerebrospinal fluid of patients with frontotemporal dementia due to P301L and G272V tau mutations. , 2003, Archives of neurology.

[30]  M. Spiegel-Adolf,et al.  Cerebrospinal fluid. , 1965, Progress in neurology and psychiatry.

[31]  M. Vandermeeren,et al.  Detection of tau proteins in normal and Alzheimer's disease cerebrospinal fluid with a sensitive sandwich enzyme-linked immunosorbent assay. , 1993, Journal of neurochemistry.

[32]  K. Blennow,et al.  Quantification of tau phosphorylated at threonine 181 in human cerebrospinal fluid: a sandwich ELISA with a synthetic phosphopeptide for standardization , 2000, Neuroscience Letters.

[33]  K. Blennow,et al.  Cerebrospinal fluid total tau as a marker of Alzheimer's disease intensity , 2010, International journal of geriatric psychiatry.

[34]  W. M. van der Flier,et al.  Amyloid-beta(1-42), total tau, and phosphorylated tau as cerebrospinal fluid biomarkers for the diagnosis of Alzheimer disease. , 2010, Clinical chemistry.

[35]  M. Weiner,et al.  Cerebrospinal fluid and plasma biomarkers in Alzheimer disease , 2010, Nature Reviews Neurology.

[36]  H. Merritt,et al.  The cerebrospinal fluid , 1935 .

[37]  R. Kandimalla,et al.  Cerebrospinal fluid profile of amyloid β42 (Aβ42), hTau and ubiquitin in North Indian Alzheimer's disease patients , 2011, Neuroscience Letters.

[38]  Katharina Buerger,et al.  Large‐scale, multicenter study of cerebrospinal fluid tau protein phosphorylated at serine 199 for the antemortem diagnosis of Alzheimer's disease , 2001, Annals of neurology.

[39]  J. Trojanowski,et al.  Biopsy-derived adult human brain tau is phosphorylated at many of the same sites as Alzheimer's disease paired helical filament tau , 1994, Neuron.