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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

Chronological relationship among pathology, clinical symptoms and biomarkers. Based on biomarker studies, Ab accumulation appears to start more than 20 years before the onset of dementia. Amyloid positron emission tomography (PET) or a decrease in CSF Aβ1-42 levels may indicate Ab accumulation in the brain, even in preclinical stage of AD. Neocortical tau pathology correlates with the timing of symptom onset and start approximately 10 years before the onset of dementia. However, these findings need to be reconciled with reports that tau pathology is observed in the prior to Ab pathology. FDG, 2-[18F]-fluoro-2-deoxy-D-glucose; MCI, mild cognitive impairment. 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 1: Chronological relationship among pathology, clinical symptoms and biomarkers. Based on biomarker studies, Ab accumulation appears to start more than 20 years before the onset of dementia. Amyloid positron emission tomography (PET) or a decrease in CSF Aβ1-42 levels may indicate Ab accumulation in the brain, even in preclinical stage of AD. Neocortical tau pathology correlates with the timing of symptom onset and start approximately 10 years before the onset of dementia. However, these findings need to be reconciled with reports that tau pathology is observed in the prior to Ab pathology. FDG, 2-[18F]-fluoro-2-deoxy-D-glucose; MCI, mild cognitive impairment. 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: Alzheimer's disease (AD), a progressive neurodegenerative disorder, is the most common form of irreversible dementia, and it carries with it a considerable human, social and economic burden. Following the onset of pathological changes in the brain that include the progressive accumulation in the CNS of amyloid beta (Aβ) deposits and neurofibrillary tangles (NFTs) formed by pathological tau, which is thought to begin more than 15 (Aβ) to 10 (NFTs) years before cognitive impairments become clinically manifest, AD patients primarily develop progressive deterioration of episodic memory and a global decline in their cognitive functions. Among several mechanistic and pathological substrates that contribute to the gradual progression of AD over time, the major neuropathological substrates of AD are the aggregation and accumulation of misfolded Aβ and the intracellular deposition of fibrillized and hyperphosphorylated tau proteins (Fig. 1).


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)

Chronological relationship among pathology, clinical symptoms and biomarkers. Based on biomarker studies, Ab accumulation appears to start more than 20 years before the onset of dementia. Amyloid positron emission tomography (PET) or a decrease in CSF Aβ1-42 levels may indicate Ab accumulation in the brain, even in preclinical stage of AD. Neocortical tau pathology correlates with the timing of symptom onset and start approximately 10 years before the onset of dementia. However, these findings need to be reconciled with reports that tau pathology is observed in the prior to Ab pathology. FDG, 2-[18F]-fluoro-2-deoxy-D-glucose; MCI, mild cognitive impairment. 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 1: Chronological relationship among pathology, clinical symptoms and biomarkers. Based on biomarker studies, Ab accumulation appears to start more than 20 years before the onset of dementia. Amyloid positron emission tomography (PET) or a decrease in CSF Aβ1-42 levels may indicate Ab accumulation in the brain, even in preclinical stage of AD. Neocortical tau pathology correlates with the timing of symptom onset and start approximately 10 years before the onset of dementia. However, these findings need to be reconciled with reports that tau pathology is observed in the prior to Ab pathology. FDG, 2-[18F]-fluoro-2-deoxy-D-glucose; MCI, mild cognitive impairment. 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: Alzheimer's disease (AD), a progressive neurodegenerative disorder, is the most common form of irreversible dementia, and it carries with it a considerable human, social and economic burden. Following the onset of pathological changes in the brain that include the progressive accumulation in the CNS of amyloid beta (Aβ) deposits and neurofibrillary tangles (NFTs) formed by pathological tau, which is thought to begin more than 15 (Aβ) to 10 (NFTs) years before cognitive impairments become clinically manifest, AD patients primarily develop progressive deterioration of episodic memory and a global decline in their cognitive functions. Among several mechanistic and pathological substrates that contribute to the gradual progression of AD over time, the major neuropathological substrates of AD are the aggregation and accumulation of misfolded Aβ and the intracellular deposition of fibrillized and hyperphosphorylated tau proteins (Fig. 1).

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