Center for Cognitive Health

Center for Cognitive Health

Parkinson’s Disease and Dementia with Lewy Bodies: Could Molecule ATH-1017 Show Efficacy for Treatment of Each?

Dementia with Lewy bodies (DLB), Parkinson’s disease (PD), and Parkinson’s disease dementia (PDD) are all neurodegenerative diseases embodied under Lewy Body disorders and have significant overlap in their pathologies, symptoms, and prognoses. Although closely related, these diseases have unique enough criteria to differentiate between them. Parkinson’s disease and DLB have identical pathologies, but early cognitive symptoms are associated with DLB over PD. Furthermore, if dementia occurs before, concurrently, or within 1 year of motor parkinsonism, DLB is diagnosed. If dementia occurs more than 1 year after an established PD diagnosis, then PDD is diagnosed. 

Both PDD and DLB typically follow the same Alzheimer’s disease (AD) dementia stages and nearly all PD patients experience some degree of cognitive deficit. Pathologically, PD is characterized by neurodegeneration and the formation of Lewy bodies (i.e., made up of misfolded alpha-synuclein) first in brainstem neurons, and then cortical structures as the disease advances. Cognitive deficits in PD are associated with deficits in various neurotransmitters (NT), with a deficiency of dopamine as the principal abnormality. Cognitive deficits are less common in PD when tremor is observed at onset, or in those with tremor predominant syndrome. Most common forms of neuropsychological deficits observed with PD involve executive dysfunction or mild subcortical dementia exemplified by difficulty in word list generation, organizational skills, and multi-tasking. 

Like PD, DLB is associated with Lewy bodies in the brainstem. However, those with DLB tend to have Lewy bodies in the substantia nigra to a lesser severity than patients with PD. Preferentially, with DLB, Lewy bodies are present in the cortex (e.g., limbic and paralimbic regions), with neocortical participation most severe in the temporal lobe. AD-type pathology is also seen, with senile plaque and neurofibrillary tangle deposition, regional neuronal loss, synapse loss, and NT deficits. Common cognitive deficits in DLB include delusions, hallucinations, fluctuating cognition/attention, REM sleep behavior disorder, depression, memory impairment, and disturbances in executive function. Parkinsonism in DLB consists of rigidity, bradykinesia, and dystonia, with rest tremor less frequent. 

Promising treatments for AD, PDD, and DLB tends to focus on therapeutic strategies that target neurotrophic factors to induce protection of existing neurons, promotion of synaptogenesis, neuronal growth, and regenerative mechanisms, which in turn, anticipates improved cognition, decreased inflammation, and improved cerebral blood flow; slowing the progression of neurodegeneration and negative effects that stem from it. Specifically, a small molecule approach that allows passage through the blood brain barrier and reaches all regions of the brain is a superior strategy in comparison to other non-efficient and invasive deliveries to the brain. Due to the stark overlap in these diseases, a medication used for AD may soon prove efficacious for the Lewy Body disorders as well.

A molecule known as ATH-1017 has potential promise for treatment of AD and may have efficacy for PD and DLB as well. ATH-1017 facilitates progress of hepatic growth factor (HGF) function and enables signal transduction through MET phosphorylation. Both HGF and MET activity in the central nervous system incorporate neuroprotective and neurotrophic effects, as well as modulation of neurogenesis and neuronal maturation. Findings suggest that ATH-1017 therapy has potential for pro-cognitive effects in those with AD, and now research is being conducted on the effects it may have on those with PDD or DLB, as there are many shared pathological characteristics between these disorders. Here at the Center for Cognitive Health, we offer clinical trials for PD/DLB and AD assessing the effects of ATH-1017. If interested, give us a call at 503-207-2066 or visit Our Webpage, where you can find a listing of all of the clinical trials being held at the Center.

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References 
 
Cummings, J., Mega, M. (2003). Neuropsychiatry and behavioral neuroscience. Oxford University Press. 
 
Athira Pharma. (2022). Are You or Someone You Know Living with Parkinson’s Disease Dementia or Dementia with Lewy Bodies? Consider Participating in the SHAPE Trial. Shape Trial. https://shapetrial.com/