Alzheimer Disease: Various Therapeutic Interventions and Alternative under Clinical Trial

This chapter describes the common therapeutic targets, approaches to clinical trial design, biomarkers, and therapeutic interventions across neurodegenerative disorders (NDDs). Each unique NDD-Alzheimer’s disease (AD), Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS), etc.-has a unique phenotype associated with the regional cell population most affected. Each disease, however, is associated with protein misfolding, oxidation, inflammation, apoptosis, and cell death. If vulnerable cell populations include transmitter source nuclei, transmitter deficits also emerge (e.g. cholinergic abnormalities in AD and dopaminergic deficits in PD). Biomarkers show regionally appropriate brain atrophy or process-related cerebrospinal deficits. Clinical trial designs share features for symptomatic interventions (e.g. cholinesterase inhibitors in AD and dopamine agents in PD) and disease-modifying therapies. Biomarkers play similar roles in trials for NDD, including demonstrating target engagement and supporting disease modification. No disease-modifying therapies have been approved for any NDDs; all programs face similar pharmacokinetic, pharmacodynamic, and regulatory challenges in therapeutic development.

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Microglia in Brain Development, Homeostasis, and Neurodegeneration

Annual Review of Genetics ◽

10.1146/annurev-genet-112618-043515 ◽

2019 ◽

Vol 53 (1) ◽

pp. 263-288 ◽

Cited By ~ 10

Author(s):

Christopher J. Bohlen ◽

Brad A. Friedman ◽

Borislav Dejanovic ◽

Morgan Sheng

Keyword(s):

Alzheimer Disease ◽

Brain Development ◽

Neurodegenerative Disease ◽

Human Genetics ◽

Association Studies ◽

Therapeutic Interventions ◽

Genome Wide Association Studies ◽

Expression Studies ◽

Genome Wide ◽

Gene Expression Studies

Advances in human genetics have implicated a growing number of genes in neurodegenerative diseases, providing insight into pathological processes. For Alzheimer disease in particular, genome-wide association studies and gene expression studies have emphasized the pathogenic contributions from microglial cells and motivated studies of microglial function/dysfunction. Here, we summarize recent genetic evidence for microglial involvement in neurodegenerative disease with a focus on Alzheimer disease, for which the evidence is most compelling. To provide context for these genetic discoveries, we discuss how microglia influence brain development and homeostasis, how microglial characteristics change in disease, and which microglial activities likely influence the course of neurodegeneration. In all, we aim to synthesize varied aspects of microglial biology and highlight microglia as possible targets for therapeutic interventions in neurodegenerative disease.

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Comparison of three therapeutic interventions for chronic constipation in paediatric patients with cerebral palsy: a randomised clinical trial

Gastroenterology Review ◽

10.5114/pg.2019.84872 ◽

2019 ◽

Vol 14 (4) ◽

pp. 292-297 ◽

Cited By ~ 1

Author(s):

Mohammad Hadi Imanieh ◽

Mohammad Reza Golpayegan ◽

Mostafa Sedighi ◽

Kamal Ahmadi ◽

Abbas Aghaie ◽

...

Keyword(s):

Clinical Trial ◽

Cerebral Palsy ◽

Chronic Constipation ◽

Randomised Clinical Trial ◽

Therapeutic Interventions ◽

Paediatric Patients

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Clinical Trial Design Issues in Mild to Moderate Alzheimer Disease

Cognitive and Behavioral Neurology ◽

10.1097/wnn.0b013e318190cf75 ◽

2008 ◽

Vol 21 (4) ◽

pp. 197-201 ◽

Cited By ~ 20

Author(s):

David S. Knopman

Keyword(s):

Clinical Trial ◽

Alzheimer Disease ◽

Trial Design ◽

Clinical Trial Design ◽

Design Issues

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Clinical trial of an inhibitor of RAGE-A interactions in Alzheimer disease

Neurology ◽

10.1212/wnl.0000000000000364 ◽

2014 ◽

Vol 82 (17) ◽

pp. 1536-1542 ◽

Cited By ~ 101

Author(s):

D. Galasko ◽

J. Bell ◽

J. Y. Mancuso ◽

J. W. Kupiec ◽

M. N. Sabbagh ◽

...

Keyword(s):

Clinical Trial ◽

Alzheimer Disease

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Neurotrophic approach in preventive therapy of alzheimer disease

European Psychiatry ◽

10.1016/s0924-9338(11)72195-2 ◽

2011 ◽

Vol 26 (S2) ◽

pp. 488-488

Author(s):

S. Gavrilova ◽

I. Kolykhalov ◽

Y. Fedorova ◽

M. Odinak ◽

A. Emelin ◽

...

Keyword(s):

Clinical Trial ◽

Alzheimer Disease ◽

Cognitive Deficit ◽

Diagnostic Category ◽

Preventive Therapy ◽

Long Term Effects ◽

Clinical Scales ◽

Slowing Down ◽

Ad Therapy

IntroductionDuring the last years a great number of new facts of involving nerve growth factors (NGF) in pathogenesis of Alzheimer Disease (AD) and other neurodegenerative diseases have been received. Discovery of neurotrophic effects of Cerebrolysin similar to NGF attracted new attention to it (Rockenstein E. et al. 2000).Clinical study of long-term effects of Cerebrolysin has proved that Cerebrolysin has positive modifying action on the dementia progression (Gavrilova S.I. et al., 2003). That's why we suggest that Cerebrolysin may prevent or slow down clinical manifestation of dementia in patients with mild cognitive impairment (MCI) of amnestic type.The aim of the present study was to investigate in an open comparative prospective clinical trial ability of Cerebrolysin to slow down or prevent transition of MCI syndrome into the clinically evident AD in 2 groups of patients repeatedly treated with 1 month courses of Cerebrolysin or Cavinton during a period of 3 years.Methods110 patients who met the diagnostic criteria of MCI of amnestic typewere included. During the clinical trial patients were assessed with a set of clinical scales and a battery of neuropsychological cognitive tests. Genotyping for the APOE polymorphism was performed as well.ResultsThe superiority of Cerebrolysin over Cavinton in slowing down of the cognitive deficit progression and delaying the time or transition of MCI patients to the diagnostic category of Alzheimer disease during 3 years was demonstrated. Cerebrolysin was particularly effective in MCI patients with the ApoE4 (+) genotype.ConclusionCerebrolysin could be recommended as a preventive AD therapy.

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Using Direct-to-Consumer Genetic Testing Results to Accelerate Alzheimer Disease Clinical Trial Recruitment

Alzheimer Disease & Associated Disorders ◽

10.1097/wad.0000000000000421 ◽

2020 ◽

Vol Publish Ahead of Print ◽

Author(s):

Mary M. Ryan ◽

Chelsea G. Cox ◽

Megan Witbracht ◽

Dan Hoang ◽

Daniel L. Gillen ◽

...

Keyword(s):

Clinical Trial ◽

Genetic Testing ◽

Alzheimer Disease ◽

Trial Recruitment ◽

Direct To Consumer ◽

Clinical Trial Recruitment

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Reasons for Failed trials of Disease-modifying Treatments for Alzheimer Disease and their Contribution in Recent Research

10.20944/preprints201909.0270.v1 ◽

2019 ◽

Author(s):

Konstantina G. Yiannopoulou ◽

Aikaterini I. Anastasiou ◽

Venetia Zachariou ◽

SH Pelidou

Keyword(s):

Clinical Trial ◽

Clinical Trials ◽

Alzheimer Disease ◽

Drug Development ◽

Inappropriate Drug ◽

Trial Methodology ◽

Prodromal Ad ◽

Csf Biomarker ◽

Disease Modifying ◽

Drug Development Research

Despite all scientific efforts and many protracted and expensive clinical trials, no new drug has been approved by FDA for treatment of Alzheimer disease (AD) since 2003. Indeed, more than 200 investigational programs have failed or have been abandoned in the last decade. The most probable explanations for failures of disease-modifying treatments (DMTs) for AD may include late initiation of treatments during the course of AD development, inappropriate drug dosages, erroneous selection of treatment targets, and mainly an inadequate understanding of the complex pathophysiology of AD, which may necessitate combination treatments rather than monotherapy. Clinical trials’ methodological issues have also been criticized. Current drug-development research for AD is aimed to overcome these drawbacks. Preclinical and prodromal AD populations, as well as traditionally investigated populations representing all the clinical stages of AD, are included in recent trials. Systematic use of biomarkers in staging preclinical and prodromal AD and of a single primary outcome in trials of prodromal AD are regularly integrated. The application of amyloid, tau, and neurodegeneration biomarkers, including new biomarkers—such as Tau positron emission tomography, neurofilament light chain (blood and CSF biomarker of axonal degeneration) and neurogranin (CSF biomarker of synaptic functioning)—to clinical trials allows more precise staging of AD. Additionally, use of the Bayesian statistics, modifiable clinical trial designs, and clinical trial simulators enrich the trial methodology. Besides, combination therapy regimens are currently assessed in clinical trials. The abovementioned diagnostic and statistical advances, which have been recently integrated in clinical trials, are consequential to the recent failures of studies of disease-modifying treatments. Their experiential rather than theoretical origins may better equip potentially successful drug-development strategies.

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