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Related Experiment Videos

Preclinical AD Workgroup staging: pathological correlates and potential challenges.

Gregory A Jicha1, Erin L Abner, Frederick A Schmitt

  • 1Neurology, University of Kentucky College of Medicine, Lexington, KY 40536, USA.

Neurobiology of Aging
|April 22, 2011
PubMed
Summary

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Preclinical Development: Overview01:28

Preclinical Development: Overview

Preclinical development consists of a series of tests that ensure the safety and efficacy of a new therapeutic compound before it is tested in humans. There are four main phases to this process. First, safety pharmacology tests are conducted to ensure the drug does not produce any acutely harmful effects. These tests examine parameters such as bronchoconstriction, cardiac dysrhythmias, blood pressure changes, and ataxia. Next, preliminary toxicological testing is performed to determine the...

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Many cognitively intact elderly individuals show signs of preclinical Alzheimer's disease (pAD), particularly amyloid pathology with early neurodegeneration. However, neocortical neurofibrillary tangles, not amyloid, are key to cognitive decline, complicating pAD staging.

Area of Science:

  • Neuropathology
  • Neurodegenerative Diseases
  • Geriatric Medicine

Background:

  • The National Institute on Aging Preclinical Alzheimer's Disease Workgroup (PADW) proposed 3 stages for preclinical Alzheimer's disease (pAD).
  • Understanding neuropathological correlates of these proposed stages is crucial for accurate classification and research.

Purpose of the Study:

  • To examine the PADW recommendations against neuropathological findings in cognitively intact elderly individuals.
  • To assess the prevalence of pAD and its stages based on neuropathology in autopsy samples.

Main Methods:

  • Analysis of neuropathological features in 126 cognitively intact elderly individuals (mean age 83.7 years) autopsied within one year of cognitive testing.
  • Correlation of observed pathologies with hypothetical PADW preclinical Alzheimer's disease stages.

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Main Results:

  • 43% (53/126) of cognitively intact individuals met criteria for pAD, with most (48%) in the proposed 'stage 3' (amyloid + early neurodegeneration).
  • Neocortical neurofibrillary tangles, not amyloid, were identified as the key pathological event preceding cognitive impairment, suggesting Braak stages III-IV are not indicative of intermediate AD likelihood.
  • Comorbid pathologies like hippocampal sclerosis, alpha-synucleinopathy, and cerebrovascular disease can influence cognitive status and confound PADW stage application.

Conclusions:

  • The PADW staging system requires neuropathological validation, particularly regarding the role of neurofibrillary tangles versus amyloid.
  • Comorbid brain pathologies significantly impact cognitive function in the elderly and must be considered when applying pAD classifications.
  • Neuropathological examination is essential for refining preclinical Alzheimer's disease definitions and understanding disease progression.