A Paradigm Shift for Evaluating Pharmacotherapy for Alzheimer's Disease: The 10-Patient Screening Protocol
Objective: Discuss etiology of Alzheimer's disease (AD) and offer a paradigm shift—a change in basic assumptions—from present standards in clinical trials.
Data Source: PubMed search for studies into AD pathophysiology and assessment of disease progression. Searched terms: amyloid precursor protein/amyloid beta pathology, senile plaques, mitochondrial dysfunction, reactive oxygen species , advanced glycation end products, neuro-inflammation, dysfunctional microglia/astrocytes, proinflammatory cytokines, ApoE4 allele, Tau phosphorylation, Chlamydia pneumoniae, Dementia Severity Rating Scale, Clinical Dementia Rating Scale, Relative's Assessment of Global Symptomatology-Elderly, and Alzheimer's Disease Assessment Scale-cognitive.
Study Selection: All prospective, randomized, placebo- or cohort-controlled, peer-reviewed English language publications from 1980 to 2012. Studies in animals, AD patients, and AD brain specimens.
Data Extraction: Objectives, methods, statistical design, and results reviewed to assess soundness of trials and validity of results. Trials with flawed methods or uninterpretable results excluded.
Data Synthesis: Primary pathophysiology comprises: amyloid precursor protein/amyloid beta pathology with deposition of senile plaques; mitochondrial dysfunction with insufficient ATP synthesis and release of reactive oxygen species; oxidative stress; and neuro-inflammation from dysfunction of microglia and astrocytes. Other factors include abnormal ApoE4 allele protein and aberrant Tau phosphorylation. Role of Chlamydia pneumoniae is unproven. Dementia Severity Rating Scale (DSRS) is optimal assessment tool for assessing AD progression. Conclusion: AD's complex pathophysiology may require polypharmacy to mitigate symptoms and progression. DSRS-driven, 10-patient pilot studies offer practical, valid, and reliable screening for potentially effective pharmacotherapy in AD. The simplicity of this paradigm shift should expedite research and may promote earlier discovery of effective pharmacotherapy for AD.
Data Source: PubMed search for studies into AD pathophysiology and assessment of disease progression. Searched terms: amyloid precursor protein/amyloid beta pathology, senile plaques, mitochondrial dysfunction, reactive oxygen species , advanced glycation end products, neuro-inflammation, dysfunctional microglia/astrocytes, proinflammatory cytokines, ApoE4 allele, Tau phosphorylation, Chlamydia pneumoniae, Dementia Severity Rating Scale, Clinical Dementia Rating Scale, Relative's Assessment of Global Symptomatology-Elderly, and Alzheimer's Disease Assessment Scale-cognitive.
Study Selection: All prospective, randomized, placebo- or cohort-controlled, peer-reviewed English language publications from 1980 to 2012. Studies in animals, AD patients, and AD brain specimens.
Data Extraction: Objectives, methods, statistical design, and results reviewed to assess soundness of trials and validity of results. Trials with flawed methods or uninterpretable results excluded.
Data Synthesis: Primary pathophysiology comprises: amyloid precursor protein/amyloid beta pathology with deposition of senile plaques; mitochondrial dysfunction with insufficient ATP synthesis and release of reactive oxygen species; oxidative stress; and neuro-inflammation from dysfunction of microglia and astrocytes. Other factors include abnormal ApoE4 allele protein and aberrant Tau phosphorylation. Role of Chlamydia pneumoniae is unproven. Dementia Severity Rating Scale (DSRS) is optimal assessment tool for assessing AD progression. Conclusion: AD's complex pathophysiology may require polypharmacy to mitigate symptoms and progression. DSRS-driven, 10-patient pilot studies offer practical, valid, and reliable screening for potentially effective pharmacotherapy in AD. The simplicity of this paradigm shift should expedite research and may promote earlier discovery of effective pharmacotherapy for AD.
Keywords: AD = Alzheimer's disease; ADR = Adverse drug reaction; AGE = Advanced glycation end-products; APP/Aβ = Amyloid precursor protein/amyloid beta; ATP = Adenosine triphosphate; Alzheimer's disease; CDR = Washington University Clinical Dementia Rating scale; CP = Chlamydia pneumoniae; DSRS = Dementia Severity Rating Scale; Dementia; FDG = Fluorodexoyglucose; MMSE = Mini-Mental State Examination; Microglial dysfunction; Neuroinflammation; Neurophysiology; PET = Positron emission tomography; Pharmacotherapy; Polypharmacy; RAGE = Receptor for advanced glycation end products; ROS = Reactive oxygen species; Reactive Oxygen Species; Research; Screening; Tau phosphorylation
Document Type: Research Article
Publication date: 01 July 2013
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