Changes in CSF cholinergic biomarkers in response to cell therapy with NGF in patients with Alzheimer's disease

Alzheimers Dement. 2015 Nov;11(11):1316-28. doi: 10.1016/j.jalz.2014.11.008. Epub 2015 Feb 9.

Abstract

Introduction: The extensive loss of central cholinergic functions in Alzheimer's disease (AD) brain is linked to impaired nerve growth factor (NGF) signaling. The cardinal cholinergic biomarker is the acetylcholine synthesizing enzyme, choline acetyltransferase (ChAT), which has recently been found in cerebrospinal fluid (CSF). The purpose of this study was to see if EC-NGF therapy will alter CSF levels of cholinergic biomarkers, ChAT, and acetylcholinesterase.

Method: Encapsulated cell implants releasing NGF (EC-NGF) were surgically implanted bilaterally in the basal forebrain of six AD patients for 12 months and cholinergic markers in CSF were analyzed.

Results: Activities of both enzymes were altered after 12 months. In particular, the activity of soluble ChAT showed high correlation with cognition, CSF tau and amyloid-β, in vivo cerebral glucose utilization and nicotinic binding sites, and morphometric and volumetric magnetic resonance imaging measures.

Discussion: A clear pattern of association is demonstrated showing a proof-of-principle effect on CSF cholinergic markers, suggestive of a beneficial EC-NGF implant therapy.

Keywords: Acetyl cholinesterase; Alzheimer's disease; Amyloid-β; Choline acetyltransferase; MRI; Nerve growth factor; Nicotine receptors; PET; tau.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylcholinesterase / cerebrospinal fluid*
  • Aged
  • Alzheimer Disease / cerebrospinal fluid*
  • Alzheimer Disease / diagnostic imaging
  • Alzheimer Disease / pathology
  • Alzheimer Disease / therapy*
  • Amyloid beta-Peptides / cerebrospinal fluid
  • Biomarkers / cerebrospinal fluid
  • Brain / diagnostic imaging
  • Brain / metabolism
  • Brain / pathology
  • Brain / surgery
  • Cell Transplantation
  • Choline O-Acetyltransferase / cerebrospinal fluid*
  • Cognition / physiology
  • Female
  • Genetic Therapy / methods
  • Glucose / metabolism
  • Humans
  • Male
  • Middle Aged
  • Nerve Growth Factor / genetics
  • Nerve Growth Factor / metabolism*
  • Radionuclide Imaging
  • Tissue Scaffolds
  • Treatment Outcome
  • tau Proteins / cerebrospinal fluid

Substances

  • Amyloid beta-Peptides
  • Biomarkers
  • MAPT protein, human
  • tau Proteins
  • Nerve Growth Factor
  • Choline O-Acetyltransferase
  • Acetylcholinesterase
  • Glucose