Elucidating the Role of Cholinergic Degeneration in Cognitive Fluctuations in Lewy Body Dementia
Trial Snapshot
- Phase
- Phase 4
- Status
- Recruiting
- Enrollment
- 120
- Locations
- 1
- Primary Endpoint
- Clinical Assessment of Fluctuations (CAF) (frequency and duration score)
Study Overview
Brief Summary
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
Detailed Description
Aim 1 is a cross-sectional case control study in which cholinergic degeneration in 45 participants with DLB or PDD with CF will be compared to a group of 45 individuals with Lewy Body disease without CF and 30 healthy controls. The first 20 participants who are eligible for Aim 2 and consent will also participate in an 8-week pre-post interventional cohort study immediately following Aim 1 procedures. For Aim 3, Aim 1 participants will complete annual follow-up evaluations for 2 years to understand factors influencing the change in cognitive fluctuations over time.
Study Design
- Study Type
- Interventional
- Allocation
- Non Randomized
- Intervention Model
- Parallel
- Primary Purpose
- Basic Science
- Masking
- None
Eligibility Criteria
- Ages
- 50 Years to 89 Years (Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- Yes
Inclusion Criteria
- •Age range: 50 ≤ age <
- •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
- •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
- •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 <
- •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
Arms & Interventions
Subjects with DLB or PDD
90 subjects with Dementia with Lewy Bodies (DLB) or Parkinson's Disease with Dementia (PDD)
Intervention: Syn-One skin biopsy (Procedure)
Subjects with DLB or PDD
90 subjects with Dementia with Lewy Bodies (DLB) or Parkinson's Disease with Dementia (PDD)
Intervention: Multi modal MRI (Diagnostic Test)
Subjects with DLB or PDD
90 subjects with Dementia with Lewy Bodies (DLB) or Parkinson's Disease with Dementia (PDD)
Intervention: Assessment of dynamic EEG features over 48-hour periods across all study aims (Diagnostic Test)
Subjects with DLB or PDD
90 subjects with Dementia with Lewy Bodies (DLB) or Parkinson's Disease with Dementia (PDD)
Intervention: Plasma biomarkers (Diagnostic Test)
Subjects with Lewy Body disease with CF
A subset of 20 subjects with Lewy Body (LB) disease with Cognitive fluctuations (CF)
This arm will be a subset of 20 subjects from Arm #1 (Subjects with DLB or PDD).
Intervention: Multi modal MRI (Diagnostic Test)
Subjects with Lewy Body disease with CF
A subset of 20 subjects with Lewy Body (LB) disease with Cognitive fluctuations (CF)
This arm will be a subset of 20 subjects from Arm #1 (Subjects with DLB or PDD).
Intervention: Assessment of dynamic EEG features over 48-hour periods across all study aims (Diagnostic Test)
Subjects with Lewy Body disease with CF
A subset of 20 subjects with Lewy Body (LB) disease with Cognitive fluctuations (CF)
This arm will be a subset of 20 subjects from Arm #1 (Subjects with DLB or PDD).
Intervention: Galantamine HBr extended-release 8mg capsules (8mg ER). (Drug)
Healthy control subjects
30 healthy controls
Intervention: Multi modal MRI (Diagnostic Test)
Healthy control subjects
30 healthy controls
Intervention: Assessment of dynamic EEG features over 48-hour periods across all study aims (Diagnostic Test)
Healthy control subjects
30 healthy controls
Intervention: Plasma biomarkers (Diagnostic Test)
Outcomes
Primary Outcomes
Clinical Assessment of Fluctuations (CAF) (frequency and duration score)
Time Frame: Screening, Baseline, ChEI Cohort Day 56, 1 year follow-up visit, and 2 year follow-up visit
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
Dementia Cognitive Fluctuations Scale-Research Version (DCFS-R) (total score)
Time Frame: Screening, Baseline, ChEI Cohort Day 56, 1 year follow-up visit, and 2 year follow-up visit
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.
Mayo Fluctuations Scale (Four questions)
Time Frame: Screening, Baseline, ChEI Cohort Day 56, 1 year follow-up visit, and 2 year follow-up visit
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.
Functional Activities Questionnaire (FAQ Assessment)
Time Frame: Screening, Baseline, 1 year follow-up visit, and 2 year follow-up visit
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.
Movement Disorder Society Unified Parkinson Disease Rating Scale (MDS-UPDRS)
Time Frame: Screening, Baseline, 1 year follow-up visit, and 2 year follow-up visit
The MDS-UPDRS is a tool that measures the experiences of daily living (Part I), motor experiences of daily living (Part II), motor examination (Part III), and motor complications (Part IV). Scores range from 0 to 260, with 0 indicating no disability and higher scores indicating greater disability. The individual parts are rated on a scale of 0 to 4, with higher scores indicating greater impairment.
REM Sleep Behavior Disorder Questionnaire (RBDSQ)
Time Frame: Screening, Baseline, 1 year follow-up visit, and 2 year follow-up visit
The RBDSQ is measured by a total from 0-13, with a score of 5 or higher indicating a positive result for REM Sleep Behavior Disorder (RBD). The questionnaire is a 10-item self-rating tool to screen for RBD, and the cutoff score can vary depending on the population being screened.
Neuropsychiatric Inventory (NPI)
Time Frame: Screening, Baseline, 1 year follow-up visit, and 2 year follow-up visit
The NPI is an interview performed with a caregiver to assess any changes in the participants' behavior related to delusions, hallucinations, anxiety, and apathy. It is comprised of 4 main questions, 31 sub-questions and frequency/severity ratings.
Enhanced Scale for the assessment for Parkinson's Disease (SAPS-PD)
Time Frame: Screening, Baseline, 1 year follow-up visit, and 2 year follow-up visit
The eSAPS-PD is used to measure the severity of hallucinations and delusions in patients with Parkinson's Disease Psychosis (PDP). Scored on a scale of 0 to 5 for each of its 9 items, resulting in a total score from 0 to 45. Each item is rated based on the severity of the symptom, with a score of 0 meaning "None" and a score of 5 meaning "Severe".
Patient Health Questionnaire-9 (PHQ-9)
Time Frame: Screening, Baseline, 1 year follow-up visit, and 2 year follow-up visit
The PHQ-9 is a self-report measure used to screen for and assess the severity of depression in adults. It consists of nine questions based on the diagnostic criteria for major depressive disorder in the DSM-5. The total score for the PHQ-9 can range from 0 to 27. Each of the nine items is scored based on the frequency with which a person has experienced a specific symptom over the past two weeks: 0: Not at all, 1: Several days, 2: More than half the days, 3: Nearly every day. The scores for all nine items are added together to produce a total severity score. While scores of 10 or higher have high sensitivity and specificity for identifying major depression, the PHQ-9 alone is not a diagnostic tool. A clinical interview is necessary for a definitive diagnosis.
Secondary Outcomes
No secondary outcomes reported