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Cholinergic treatment shows promise in primary progressive aphasia

Cholinesterase inhibitors, the most frequently used therapeutic agent to treat Alzheimer’s disease, appeared to help patients with primary progressive aphasia, or PPA, who have positive Alzheimer’s disease biomarkers, according to study findings.

"PPA is a devastating dementia. Patients are essentially intact in all other areas except their language for many years, and they feel this loss acutely,” Changiz Geula, PhD, of the Mesulam Cognitive Neurology and Alzheimer’s Disease Center at Northwestern University, said in a press release.

Although PPA presents with diverse dementia pathologies, the status of its cholinergic system is largely unknown, Geula and colleagues wrote in Neurology. Researchers examined the brains of 36 PPA patients with the neuropathology of Alzheimer’s disease (PPA-AD) or frontotemporal lobar degeneration with taupathy (PPA-Tau) or transactive response DNA binding protein-43 inclusions (PPA-TDP) postmortem to determine the status of the basal forebrain cholinergic neuron (BFCN) system in PPA as justification for cholinergic therapy. PPA brains were also compared with those of cognitively normal individuals.

The investigators found there was severe and selective BFCN degeneration as well as consequent depletion of cortical cholinergic axons in patients with PPA who had Alzheimer’s disease pathology.

While about 80% of PPA-AD participants (n = 11) had moderate to severe neuronal loss and gliosis in the BFCN, such pathology was observed in only 10% of PPA-TDP participants (n = 1) and in no PPA-Tau participants, according to the study results. In addition, PPA-AD participants had prominent axon loss in neural areas encompassing the language network and had greater loss in the language-dominant left hemisphere of the brain, Geula and colleagues found.

“The demonstration of cholinergic denervation with an anatomy that fits the clinical profile suggests that cholinergic treatment should be pursued in these patients,” they wrote in the full study.

In subpopulation analysis of PPA-AD participants, the researchers observed substantial tangle formation, loss of BFCN and degeneration of cortical cholinergic axons. In these participants, they also saw significant loss of p75 low affinity neurotrophine receptor-positive BFCN compared with controls (P < .01).

"The findings provide the basic scientific foundation to spur a clinical trial to test the treatment on patients with PPA,” Geula said in the release. “No one knew before that this cholinergic system is devastated in patients with PPA associated with Alzheimer’s, but we've now demonstrated that and have justified the need for clinical trials with this therapy.” – by Savannah Demko

Disclosure: The authors report no relevant financial disclosures.