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Role of cerebrospinal fluid biomarkers in clinical trials for Alzheimer's disease modifying therapies.

Kang JH, Ryoo NY, Shin DW, Trojanowski JQ, Shaw LM - Korean J. Physiol. Pharmacol. (2014)

Bottom Line: Given the growing consensus that the DMT is likely to require treatment initiation well before full-blown dementia emerges, the early detection of AD will provide opportunities to successfully identify new drugs that slow the course of AD pathology.To accomplish this, global efforts are underway to standardize CSF biomarker measurements and a quality control program supported by the Alzheimer's Association.The current review summarizes therapeutic targets of developing drugs in AD pathophysiology, and provides the most recent advances in the.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology and Clinical Pharmacology, Inha University School of Medicine, Incheon 400-712, Korea. ; Hypoxia-related Disease Research Center, Inha University School of Medicine, Incheon 400-712, Korea. ; Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.

ABSTRACT
Until now, a disease-modifying therapy (DMT) that has an ability to slow or arrest Alzheimer's disease (AD) progression has not been developed, and all clinical trials involving AD patients enrolled by clinical assessment alone also have not been successful. Given the growing consensus that the DMT is likely to require treatment initiation well before full-blown dementia emerges, the early detection of AD will provide opportunities to successfully identify new drugs that slow the course of AD pathology. Recent advances in early detection of AD and prediction of progression of the disease using various biomarkers, including cerebrospinal fluid (CSF) Aβ1-42, total tau and p-tau181 levels, and imagining biomarkers, are now being actively integrated into the designs of AD clinical trials. In terms of therapeutic mechanisms, monitoring these markers may be helpful for go/no-go decision making as well as surrogate markers for disease severity or progression. Furthermore, CSF biomarkers can be used as a tool to enrich patients for clinical trials with prospect of increasing statistical power and reducing costs in drug development. However, the standardization of technical aspects of analysis of these biomarkers is an essential prerequisite to the clinical uses. To accomplish this, global efforts are underway to standardize CSF biomarker measurements and a quality control program supported by the Alzheimer's Association. The current review summarizes therapeutic targets of developing drugs in AD pathophysiology, and provides the most recent advances in the.

No MeSH data available.


Related in: MedlinePlus

Schematic presentation of tau mediated neurodegeneration. Phosphorylation and dephosphorylation of tau control the stability of microtubule. Hyperphosphorylation of tau induces disassembly of mitrotubules, causing axonal transport failure. Unbound tau produces oligomers or aggregates which congest axonal transport, and the tau pathology is synaptically transmitted. Reproduced from [Therapeutic strategies for tau mediated neurodegneration, Yoshiyama Y, Lee VM and Trojanowski JQ, J Neruol Neurosurg Psychiatry 84:784-795, 2013] with permission from BMJ Publishing Group Ltd.
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Figure 3: Schematic presentation of tau mediated neurodegeneration. Phosphorylation and dephosphorylation of tau control the stability of microtubule. Hyperphosphorylation of tau induces disassembly of mitrotubules, causing axonal transport failure. Unbound tau produces oligomers or aggregates which congest axonal transport, and the tau pathology is synaptically transmitted. Reproduced from [Therapeutic strategies for tau mediated neurodegneration, Yoshiyama Y, Lee VM and Trojanowski JQ, J Neruol Neurosurg Psychiatry 84:784-795, 2013] with permission from BMJ Publishing Group Ltd.

Mentions: Intracellular fibrillary NFTs containing hyperphosphorylated and fibrillar species of tau are one of hallmarks of AD pathology, but they are not specific for AD. If tau is abnormally hyperphosphorylated and aggregated, it may be toxic due to gains of deleterious function or loss of the normal function of tau and microtubule instability followed by axonal transport failure (Fig. 3). There may be two approaches to inhibiting tau toxicity [11,62]. The first is the inhibition of abnormal hyperphosphorylation by targeting tau kinase and/or phosphatase. In addition, inhibitors of tau aggregation or disassemblers may be beneficial for protecting neurons from tau aggregate toxicity. There are several candidates of tau kinase and phosphatase related to tau hyperphosphorylation [63]. For example, glycogen synthase kinase 3 (GSK-3) is a well-known tau kinase, which is balanced with a phosphatase, protein phosphatase 2A. Valproic acid and lithium, well-known for the treatment of epilepsy and bipolar disorder, respectively, are GSK-3 inhibitors [64]. However, they didn't show consistent results for cognitive improvement or changes in CSF tau or p-tau181 concentration in clinical trials [65,66,67]. Several new GSK-3 inhibitors are being tested in clinical trials. NP031112 (tideglusib), which is a non-ATP competitive GSK3 inhibitor, reduces tau hyperphosphorylation and amyloid deposit, prevents neuronal death, and improves cognitive function in animal models [68]. This drug showed clinical benefits in a pilot, randomized, double-blind, placebo-controlled clinical trial, and it is currently being confirmed in a larger clinical trial [69]. Other multifunctional inhibitors of tau aggregation are also in development. Methylene blue, a famous histology dye, inhibits tau aggregation in addition to its antioxidant activity and the ability to enhance mitochondrial function. In a Phase 2, placebo-controlled study, a middle dose of methylene blue known as Rember improved cognitive function in mild-to-moderate AD patients and had evidence of slower progression of the disease [70]. Davunetide (an octapeptide) and nicotinamide are inhibitors of tau aggregation that showed prevention of cognitive deficit in AD animal models [71]. Rember is safe and tolerable and it continues in clinical studies but Davunetide failed in clinical trials for AD and other tauopathies (for a review, see http://www.alzforum.org/news/research-news/tau-targeting-drug-davunetide-washes-out-phase-3-trials).


Role of cerebrospinal fluid biomarkers in clinical trials for Alzheimer's disease modifying therapies.

Kang JH, Ryoo NY, Shin DW, Trojanowski JQ, Shaw LM - Korean J. Physiol. Pharmacol. (2014)

Schematic presentation of tau mediated neurodegeneration. Phosphorylation and dephosphorylation of tau control the stability of microtubule. Hyperphosphorylation of tau induces disassembly of mitrotubules, causing axonal transport failure. Unbound tau produces oligomers or aggregates which congest axonal transport, and the tau pathology is synaptically transmitted. Reproduced from [Therapeutic strategies for tau mediated neurodegneration, Yoshiyama Y, Lee VM and Trojanowski JQ, J Neruol Neurosurg Psychiatry 84:784-795, 2013] with permission from BMJ Publishing Group Ltd.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4296032&req=5

Figure 3: Schematic presentation of tau mediated neurodegeneration. Phosphorylation and dephosphorylation of tau control the stability of microtubule. Hyperphosphorylation of tau induces disassembly of mitrotubules, causing axonal transport failure. Unbound tau produces oligomers or aggregates which congest axonal transport, and the tau pathology is synaptically transmitted. Reproduced from [Therapeutic strategies for tau mediated neurodegneration, Yoshiyama Y, Lee VM and Trojanowski JQ, J Neruol Neurosurg Psychiatry 84:784-795, 2013] with permission from BMJ Publishing Group Ltd.
Mentions: Intracellular fibrillary NFTs containing hyperphosphorylated and fibrillar species of tau are one of hallmarks of AD pathology, but they are not specific for AD. If tau is abnormally hyperphosphorylated and aggregated, it may be toxic due to gains of deleterious function or loss of the normal function of tau and microtubule instability followed by axonal transport failure (Fig. 3). There may be two approaches to inhibiting tau toxicity [11,62]. The first is the inhibition of abnormal hyperphosphorylation by targeting tau kinase and/or phosphatase. In addition, inhibitors of tau aggregation or disassemblers may be beneficial for protecting neurons from tau aggregate toxicity. There are several candidates of tau kinase and phosphatase related to tau hyperphosphorylation [63]. For example, glycogen synthase kinase 3 (GSK-3) is a well-known tau kinase, which is balanced with a phosphatase, protein phosphatase 2A. Valproic acid and lithium, well-known for the treatment of epilepsy and bipolar disorder, respectively, are GSK-3 inhibitors [64]. However, they didn't show consistent results for cognitive improvement or changes in CSF tau or p-tau181 concentration in clinical trials [65,66,67]. Several new GSK-3 inhibitors are being tested in clinical trials. NP031112 (tideglusib), which is a non-ATP competitive GSK3 inhibitor, reduces tau hyperphosphorylation and amyloid deposit, prevents neuronal death, and improves cognitive function in animal models [68]. This drug showed clinical benefits in a pilot, randomized, double-blind, placebo-controlled clinical trial, and it is currently being confirmed in a larger clinical trial [69]. Other multifunctional inhibitors of tau aggregation are also in development. Methylene blue, a famous histology dye, inhibits tau aggregation in addition to its antioxidant activity and the ability to enhance mitochondrial function. In a Phase 2, placebo-controlled study, a middle dose of methylene blue known as Rember improved cognitive function in mild-to-moderate AD patients and had evidence of slower progression of the disease [70]. Davunetide (an octapeptide) and nicotinamide are inhibitors of tau aggregation that showed prevention of cognitive deficit in AD animal models [71]. Rember is safe and tolerable and it continues in clinical studies but Davunetide failed in clinical trials for AD and other tauopathies (for a review, see http://www.alzforum.org/news/research-news/tau-targeting-drug-davunetide-washes-out-phase-3-trials).

Bottom Line: Given the growing consensus that the DMT is likely to require treatment initiation well before full-blown dementia emerges, the early detection of AD will provide opportunities to successfully identify new drugs that slow the course of AD pathology.To accomplish this, global efforts are underway to standardize CSF biomarker measurements and a quality control program supported by the Alzheimer's Association.The current review summarizes therapeutic targets of developing drugs in AD pathophysiology, and provides the most recent advances in the.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology and Clinical Pharmacology, Inha University School of Medicine, Incheon 400-712, Korea. ; Hypoxia-related Disease Research Center, Inha University School of Medicine, Incheon 400-712, Korea. ; Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.

ABSTRACT
Until now, a disease-modifying therapy (DMT) that has an ability to slow or arrest Alzheimer's disease (AD) progression has not been developed, and all clinical trials involving AD patients enrolled by clinical assessment alone also have not been successful. Given the growing consensus that the DMT is likely to require treatment initiation well before full-blown dementia emerges, the early detection of AD will provide opportunities to successfully identify new drugs that slow the course of AD pathology. Recent advances in early detection of AD and prediction of progression of the disease using various biomarkers, including cerebrospinal fluid (CSF) Aβ1-42, total tau and p-tau181 levels, and imagining biomarkers, are now being actively integrated into the designs of AD clinical trials. In terms of therapeutic mechanisms, monitoring these markers may be helpful for go/no-go decision making as well as surrogate markers for disease severity or progression. Furthermore, CSF biomarkers can be used as a tool to enrich patients for clinical trials with prospect of increasing statistical power and reducing costs in drug development. However, the standardization of technical aspects of analysis of these biomarkers is an essential prerequisite to the clinical uses. To accomplish this, global efforts are underway to standardize CSF biomarker measurements and a quality control program supported by the Alzheimer's Association. The current review summarizes therapeutic targets of developing drugs in AD pathophysiology, and provides the most recent advances in the.

No MeSH data available.


Related in: MedlinePlus