Cholinergic degeneration and cognitive fluctuations in Lewy body dementias

Elucidating the Role of Cholinergic Degeneration in Cognitive Fluctuations in Lewy Body Dementia

This project will test whether loss of cholinergic neurons is linked to cognitive fluctuations in people with Lewy body dementias using blood and skin biomarkers, multimodal MRI, prolonged EEG, and will try an 8‑week galantamine treatment in a small subgroup.

Quick facts

• Phase: PHASE4
• Study type: Interventional
• Enrollment: 120 (estimated)
• Ages: 50 Years to 89 Years
• Sex: All
• Sponsor: Virginia Commonwealth University (other)
• Locations: 1 site (Richmond, Virginia)
• Trial ID: NCT07284290 on ClinicalTrials.gov

What this trial studies

This is a case-control study comparing measures of cholinergic degeneration in 45 people with DLB or PDD who have cognitive fluctuations, 45 people with Lewy body disease without cognitive fluctuations, and 30 healthy controls using skin biopsy, plasma biomarkers, multimodal MRI, and 48‑hour EEG monitoring. The first 20 eligible participants will also enter an 8‑week pre-post interventional cohort receiving extended‑release galantamine to see if symptoms or biomarkers change. All Aim 1 participants will be followed annually for two years to track changes in cognitive fluctuations over time. The study combines molecular, imaging, and electrophysiologic measures in the same participants to link biology with clinical fluctuation symptoms.

Who should consider this trial

Good fit: Ideal candidates are adults aged 50 to 89 with clinically probable dementia with Lewy bodies, Parkinson disease dementia, PD with mild cognitive impairment, or mild cognitive impairment with Lewy bodies who can undergo imaging, EEG, skin biopsy, blood draws, and (if eligible) an 8‑week galantamine regimen.

Not a fit: People without Lewy body disease or cognitive fluctuations, those with contraindications to the procedures or galantamine, or those unable to travel or consent are unlikely to gain direct benefit from participating.

Why it matters

Potential benefit: If successful, the work could clarify biological drivers of cognitive fluctuations and point to cholinergic-targeted treatments or better diagnostic markers for people with Lewy body dementias.

How similar studies have performed: Prior work links cholinergic loss to fluctuation symptoms and cholinesterase inhibitors like galantamine have shown symptomatic effects, but combining molecular biomarkers, long‑duration EEG, and multimodal imaging in the same participants is a novel approach.

Eligibility criteria

Inclusion Criteria:

Arm 1:

* Age range: 50 ≤ age \< 90.
* Diagnosis of dementia with Lewy bodies (DLB), Parkinson disease dementia (PDD), Parkinson disease with Mild Cognitive Impairment (PD-MCI), Mild Cognitive Impairment with Lewy bodies (MCI-LB).
* DLB participants must fulfill criteria for clinically probable DLB based on the 2017 4th consensus report of the DLB consortium.
* PDD participants must meet criteria for clinically probable PD according to the MDS Clinical Diagnostic Criteria for Parkinson's Disease and must also meet criteria for probable PDD based on the 2007 Movement Disorders Society clinical diagnostic criteria.
* PD-MCI participants must meet criteria for clinically probable PD according to the MDS Clinical Diagnostic Criteria for Parkinson's Disease and meet criteria for Mild Cognitive Impairment on cognitive testing at screening.
* MCI-LB participants with must meet established research criteria.
* Capacity to provide informed consent or, if unable, availability of a legally authorized representative or guardian who can provide informed consent.
* Availability of informant (for participants meeting criteria for dementia).
* Ability and willingness to comply with the study-related procedures.
* Fluent in spoken and written English (due to cognitive testing)

Exclusion Criteria:

Arm 1

* History of cognitive disorder or psychiatric disorder other than that related to dementia with Lewy bodies or Parkinson disease dementia.
* History of deep brain stimulation or any neurosurgical procedure.
* History of structural brain disease or known significant cerebrovascular disease.
* History of seizures or epilepsy and/or use of sodium channel blockers, i.e. carbamazepine, oxcarbazepine, phenytoin, topiramate, lamotrigine, felbamate, zonisamide, rufinamide, lacosamide, eslicarbazepine, and valproate.
* Greater than two alcoholic drinks per day for men and one per day for women.
* Regular use of benzodiazepines or barbiturates. (If benzodiazepines are taken as needed only, these medications cannot be taken within 5 half-lives of screening visit or between screening visit and EEG.)
* Severe dementia (based on PI assessment of subject dependence level for instrumental activities of daily living)
* Any contraindication to brain MRI.
* Any medical condition that would interfere with ability to complete all study procedures.
* Participants must not be pregnant, planning to become pregnant, or father a child for the duration of the study

Inclusion Criteria:

Arm 2 (Cholinesterase inhibitor cohort) inclusion criteria:

* Completed Aim 1.
* Clinical diagnosis of LBD (DLB or PDD) with CF.
* Not taking a cholinesterase inhibitor and has not taken a cholinesterase inhibitor in the previous 90 days.
* Ability and willingness to comply with the ChEI Cohort procedures (including galantamine administration), or a caregiver willing and able to ensure compliance.

Exclusion Criteria:

Arm 2 (Cholinesterase inhibitor cohort) exclusion criteria:

* Severe hepatic impairment.
* Renal failure.
* Significant bradycardia (\<50 bpm) at screening or history of AV block.
* Any contraindication to galantamine administration based on PI discretion.

Inclusion criteria:

Arm 3 (Healthy Controls)

* Age range: 50 ≤ age \< 90.
* Healthy controls should not have any known neurologic conditions that could interfere with study procedures or results.
* Capacity to provide informed consent or, if unable, availability of a legally authorized representative or guardian who can provide informed consent.
* Availability of informant (for participants meeting criteria for dementia).
* Ability and willingness to comply with the study-related procedures.
* Fluent in spoken and written English (due to cognitive testing).

Exclusion Criteria:

Arm 3 (Healthy Controls)

* No History of cognitive disorder or psychiatric disorder other than that related to dementia with Lewy bodies or Parkinson disease dementia.
* No History of deep brain stimulation or any neurosurgical procedure.
* No History of structural brain disease or known significant cerebrovascular disease.
* No History of seizures or epilepsy and/or use of sodium channel blockers, i.e. carbamazepine, oxcarbazepine, phenytoin, topiramate, lamotrigine, felbamate, zonisamide, rufinamide, lacosamide, eslicarbazepine, and valproate.
* Any medical condition that would interfere with ability to complete all study procedures.
* Participants must not be pregnant, planning to become pregnant, or father a child for the duration of the study

Where this trial is running

Richmond, Virginia

• Virginia Commonwealth University — Richmond, Virginia, United States (RECRUITING)

Study contacts

• Principal investigator: Matthew Barrett — Virginia Commonwealth University
• Study coordinator: Kara McHaney

Conditions: Dementia With Lewy Bodies, Parkinson Disease Dementia, Healthy Controls, Parkinson Disease with Mild Cognitive Impairment, Mild Cognitive Impairment with Lewy Bodies