Elucidating the Role of Cholinergic Degeneration in Cognitive Fluctuations in Lewy Body Dementia
Trial statusRecruiting
Trial phasePhase 4
Trial typeInterventional
Biological sexAll
Age50-89
SponsorVirginia Commonwealth University
About this trial
The proposed study aims to address the critical gaps in understanding the mechanisms of CF (Cognitive Fluctuations) by leveraging recently emerged molecular biomarkers, advanced neuroimaging techniques to assess measures of cholinergic degeneration, and synchronous EEG and assessments of attention. One of the overarching innovations of study is combining all of these assessments into one integrated research plan
Eligibility criteria
This trial accepts healthy volunteersQualifiers
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.
Disqualifiers
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.
Trial design
Design model
Parallel
Treatments tested in this trial
Syn-One skin biopsy
Procedure/SurgeryDetects phosphorylated alpha synuclein in cutaneous nerve fibrils which has \>95% sensitivity in detecting DLB
Multi modal MRI
Diagnostic testFunctional MRI used to investigate the network connectivity changes associated with alterations in the cholinergic system. Using this comprehensive methodology to establish cholinergic degeneration's contribution to CF provides a robust framework for future research and therapeutic strategies.
Assessment of dynamic EEG features over 48-hour periods across all study aims
Diagnostic testImplementing prolonged EEG monitoring, to capture dynamic changes in neural activity associated with CF. The methods are designed avoid the limitations identified in a systematic review of EEG studies in DLB, as will use quantitative analysis of EEG, uniformly apply diagnostic criteria, and consider the confounding effects of medications. Concurrent evaluation of PVT performance and EEG This dual assessment will correlate cognitive and neurophysiological dynamics in real-time, providing a more holistic understanding of CF over time and the functional brain activity that underlies them. Temporal integration of PVT with EEG data collection will enable the identity of specific correlates of CF.
Plasma biomarkers
Diagnostic testA blood sample will be collected and sent for processing by C2N Diagnostics for the detection of Aβ42/40 and p-tau217 via mass spectrometry, a method shown to be highly accurate for predicting amyloid positivity on PET (AUC=0.94). Exploratory Biomarkers: The additional blood sample will be used for analysis of exploratory biomarkers and future research. A total of up to 20mL of blood will be taken.
Galantamine HBr extended-release 8mg capsules (8mg ER).
Drug20 participants from the arm 1. Participants will take 1 capsule daily of galantamine 8mg ER for 4 weeks and then increase to 2 capsules daily of galantamine 8mg ER (16mg) for 4 weeks. This titration will mitigate potential for cholinergic side effects. At 2 weeks, 4 weeks and 6 weeks of the treatment period, safety and compliance will be assessed during phone call visits. Any adverse event rated as Grade 2 or greater according to the Common Terminology Criteria for Adverse Events (CTCAE) v5.0 and that is definitely or possibly attributable to the study drug will result in study drug withdrawal or dose reduction.
Treatment groups
120 Participants
are divided into 3 treatment groupsGroup A: Subjects with DLB or PDDExperimental treatment 4 interventions
Group B: Subjects with Lewy Body disease with CFActive comparator 3 interventions
Group C: Healthy control subjectsOther 3 interventions
Trial outcomes
Primary outcomes
1
Clinical Assessment of Fluctuations (CAF) (frequency and duration score)
The scoring for the Clinical Assessment of Fluctuations (CAF) is a two-step process that uses both a frequency and a duration score. The two scores are multiplied together to get the final severity rating. A higher score indicates more severe cognitive fluctuations. After rating the frequency and duration, the two scores are multiplied to get the final CAF score. Frequency score x Duration score=Total CAF score
Time frame
Screening, Baseline, ChEI Cohort Day 56, 1 year follow-up visit, and 2 year follow-up visit2
Dementia Cognitive Fluctuations Scale-Research Version (DCFS-R) (total score)
The DCFS-R is measured as a total score from 4 to 20, with higher scores indicating more severe cognitive fluctuations in dementia. It is calculated by summing a nurse's ratings on four items, each scored on a 5-point Likert scale (1=no difference, 5=very large difference). The four items assess the difference between a person's best and worst functioning, which includes daytime somnolence, drowsiness, and altered levels of consciousness.
Time frame
Screening, Baseline, ChEI Cohort Day 56, 1 year follow-up visit, and 2 year follow-up visit3
Mayo Fluctuations Scale (Four questions)
The four questions included in the Mayo Fluctuations Scale have been found to significantly differentiate Alzheimer's Disease from DLB. Positive items are summed to create a "fluctuations composite score" with a score of 3 or 4 associated with DLB.
Time frame
Screening, Baseline, ChEI Cohort Day 56, 1 year follow-up visit, and 2 year follow-up visit4
Functional Activities Questionnaire (FAQ Assessment)
The FAQ is a number from 0 to 30 that represents a person's independence in daily tasks, with higher scores indicating more difficulty. The score is calculated by summing the ratings (0-3) for 10 activities, and a cut-off score of 9 or higher is often used to suggest potential cognitive or functional impairment.
Time frame
Screening, Baseline, 1 year follow-up visit, and 2 year follow-up visitSponsors and contacts
Click on the lead sponsor to view all of their trials.
Virginia Commonwealth University
Lead sponsor
National Institute of Neurological Disorders and Stroke (NINDS)
Collaborator
Source ClinicalTrials.gov