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Fluid Biomarkers in Clinical Trials of Alzheimer's Disease Therapeutics.

Ritter A, Cummings J - Front Neurol (2015)

Bottom Line: Current treatments provide symptomatic relief but do not affect the underlying pathology of the disease.Insights gained from decades of research have begun to unlock the pathophysiology of this complex disease and have provided targets for disease-modifying therapies.Fluid biomarkers are important because they can provide information regarding the underlying biochemical processes that are occurring in the brain.

View Article: PubMed Central - PubMed

Affiliation: Cleveland Clinic Lou Ruvo Center for Brain Health , Las Vegas, NV , USA.

ABSTRACT
With the demographic shift of the global population toward longer life expectancy, the number of people living with Alzheimer's disease (AD) has rapidly expanded and is projected to triple by the year 2050. Current treatments provide symptomatic relief but do not affect the underlying pathology of the disease. Therapies that prevent or slow the progression of the disease are urgently needed to avoid this growing public health emergency. Insights gained from decades of research have begun to unlock the pathophysiology of this complex disease and have provided targets for disease-modifying therapies. In the last decade, few therapeutic agents designed to modify the underlying disease process have progressed to clinical trials and none have been brought to market. With the focus on disease modification, biomarkers promise to play an increasingly important role in clinical trials. Six biomarkers have now been included in diagnostic criteria for AD and are regularly incorporated into clinical trials. Three biomarkers are neuroimaging measures - hippocampal atrophy measured by magnetic resonance imaging (MRI), amyloid uptake as measured by Pittsburg compound B positron emission tomography (PiB-PET), and decreased fluorodeoxyglucose (18F) uptake as measured by PET (FDG-PET) - and three are sampled from fluid sources - cerebrospinal fluid levels of amyloid β42 (Aβ42), total tau, and phosphorylated tau. Fluid biomarkers are important because they can provide information regarding the underlying biochemical processes that are occurring in the brain. The purpose of this paper is to review the literature regarding the existing and emerging fluid biomarkers and to examine how fluid biomarkers have been incorporated into clinical trials.

No MeSH data available.


Related in: MedlinePlus

The amyloidogenic pathway. In the amyloidogenic pathway, The amyloid precursor protein (APP) is processed in two sequential steps: (1) in the first step, APP is cleaved by BACE1 yielding a membrane-bound fragment and releasing sAPP into the interstitial space. (2) In the second step, gamma secretase cleaves the remaining membrane-bound fragment releasing an abeta 42 fragment.
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Figure 1: The amyloidogenic pathway. In the amyloidogenic pathway, The amyloid precursor protein (APP) is processed in two sequential steps: (1) in the first step, APP is cleaved by BACE1 yielding a membrane-bound fragment and releasing sAPP into the interstitial space. (2) In the second step, gamma secretase cleaves the remaining membrane-bound fragment releasing an abeta 42 fragment.

Mentions: A picture of the complex chain of events leading to AD has emerged over the last three decades. The leading theory to explain the pathophysiological changes in AD is the amyloid cascade hypothesis (14). Based largely on models derived from familial cases of AD – in which, one of three autosomal dominantly inherited mutations results in pathological aggregation and accumulation of Aβ – the amyloid cascade hypothesis posits that the pathological accumulation of amyloid triggers a complex sequence of biochemical events ultimately leading to widespread synaptic dysfunction, neuronal dysfunction, and cell death. An overview of the initial steps involved in Aβ production is provided in Figure 1.


Fluid Biomarkers in Clinical Trials of Alzheimer's Disease Therapeutics.

Ritter A, Cummings J - Front Neurol (2015)

The amyloidogenic pathway. In the amyloidogenic pathway, The amyloid precursor protein (APP) is processed in two sequential steps: (1) in the first step, APP is cleaved by BACE1 yielding a membrane-bound fragment and releasing sAPP into the interstitial space. (2) In the second step, gamma secretase cleaves the remaining membrane-bound fragment releasing an abeta 42 fragment.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4553391&req=5

Figure 1: The amyloidogenic pathway. In the amyloidogenic pathway, The amyloid precursor protein (APP) is processed in two sequential steps: (1) in the first step, APP is cleaved by BACE1 yielding a membrane-bound fragment and releasing sAPP into the interstitial space. (2) In the second step, gamma secretase cleaves the remaining membrane-bound fragment releasing an abeta 42 fragment.
Mentions: A picture of the complex chain of events leading to AD has emerged over the last three decades. The leading theory to explain the pathophysiological changes in AD is the amyloid cascade hypothesis (14). Based largely on models derived from familial cases of AD – in which, one of three autosomal dominantly inherited mutations results in pathological aggregation and accumulation of Aβ – the amyloid cascade hypothesis posits that the pathological accumulation of amyloid triggers a complex sequence of biochemical events ultimately leading to widespread synaptic dysfunction, neuronal dysfunction, and cell death. An overview of the initial steps involved in Aβ production is provided in Figure 1.

Bottom Line: Current treatments provide symptomatic relief but do not affect the underlying pathology of the disease.Insights gained from decades of research have begun to unlock the pathophysiology of this complex disease and have provided targets for disease-modifying therapies.Fluid biomarkers are important because they can provide information regarding the underlying biochemical processes that are occurring in the brain.

View Article: PubMed Central - PubMed

Affiliation: Cleveland Clinic Lou Ruvo Center for Brain Health , Las Vegas, NV , USA.

ABSTRACT
With the demographic shift of the global population toward longer life expectancy, the number of people living with Alzheimer's disease (AD) has rapidly expanded and is projected to triple by the year 2050. Current treatments provide symptomatic relief but do not affect the underlying pathology of the disease. Therapies that prevent or slow the progression of the disease are urgently needed to avoid this growing public health emergency. Insights gained from decades of research have begun to unlock the pathophysiology of this complex disease and have provided targets for disease-modifying therapies. In the last decade, few therapeutic agents designed to modify the underlying disease process have progressed to clinical trials and none have been brought to market. With the focus on disease modification, biomarkers promise to play an increasingly important role in clinical trials. Six biomarkers have now been included in diagnostic criteria for AD and are regularly incorporated into clinical trials. Three biomarkers are neuroimaging measures - hippocampal atrophy measured by magnetic resonance imaging (MRI), amyloid uptake as measured by Pittsburg compound B positron emission tomography (PiB-PET), and decreased fluorodeoxyglucose (18F) uptake as measured by PET (FDG-PET) - and three are sampled from fluid sources - cerebrospinal fluid levels of amyloid β42 (Aβ42), total tau, and phosphorylated tau. Fluid biomarkers are important because they can provide information regarding the underlying biochemical processes that are occurring in the brain. The purpose of this paper is to review the literature regarding the existing and emerging fluid biomarkers and to examine how fluid biomarkers have been incorporated into clinical trials.

No MeSH data available.


Related in: MedlinePlus