Lewy Body Dementia With Behavioral Disturbance, Lewy Body Disease, Lewy Body Variant of Alzheimer Disease
Conditions
Keywords
Lewy Body Dementia, Cognitive, Thinking, Cognition, Cognitive Rehabilitation, Brain Stimulation, Imaging, Lewy Body, Dementia
Brief summary
Fluctuations in alertness are very common in persons with Lewy body dementias and are a major source of disability. Changes in a chemical messenger molecule called acetylcholine within certain brain regions may play a role in these fluctuations. We propose to test this hypothesis and also determine whether a non-invasive way of stimulating affected brain regions may be of relevance for future management of these fluctuations.
Detailed description
The central premise of the research study was that cholinergic system changes in specific neural network regions underlie cognitive fluctuations in patients with LBD. The cingulo-opercular task control (COTC) neural network is believed to play a role in maintenance of alertness but this remains uncertain in LDB. This critical knowledge gap formed the basis of the study's first aim. The study proposed to use transcranial direct current stimulation (tDCS) to excite critical cholinergic denervation components of the COTC as an adjunct to cholinergic pharmacotherapy in a target engagement study. tDCS is an emerging non-invasive neurostimulation technology that may improve a range of neurological symptoms, including cognition. The study evaluated whether target engagement by tDCS excitation of cholinergic denervated COTC hubs may affect cognitive fluctuations in LBD subjects. While the cingulo-opercular network was expected to be the primary site of cholinergic denervation based on preliminary evidence, and thus the focus of the stimulation intervention, the typical pattern of cholinergic denervation in our sample occurred at a temporal lobe region that is classified as a node of the ventral attention network in the Gordon atlas. Additional results from examining different networks have been added to reflect the unanticipated relocation of stimulation location.
Interventions
Participants will receive HD-tDCS at up to 4 mA per channel for 20 minutes for 10 sessions. Dose determined through individualized computational models.
Sponsors
Study design
Masking description
Investigator, Outcomes Assessor, and Participant/Care Provider will all know the participant is receiving intervention/stimulation. There is no placebo condition.
Intervention model description
Eligible participants receive individualized intervention/stimulation based on their fMRI and PET imaging.
Eligibility
Inclusion criteria
* LBD patients (DLB or PDD) who have cognitive fluctuations and who are on stable doses of cholinesterase inhibitors (i.e., at least 4 weeks) will be recruited to participate in this study. * DLB patients will meet the Fourth consensus report of the DLB Consortium inclusion criteria for probable DLB. * Subjects will be identified according to the following recognized DLB features: spontaneous parkinsonian motor signs, fluctuating attention and concentration, recurrent well-formed visual hallucinations, presence of REM behavioral sleep disturbance, anosmia/hyposmia,or autonomic dysfunction. * PDD patients will meet the criteria by Emre et al. (Cognitive deficits in at least two of four of the following cognitive domains: Impaired attention, impaired executive functions, impairment in visuo-spatial functions, impaired free recall memory typically improved with cuing. Must also meet criteria for at least one behavioral symptom: apathy, depressed or anxious mood, hallucinations, delusions, excessive daytime sleepiness). Lack of behavioral symptoms does not exclude the diagnosis. Must also have none of Group III features present: (1) Co-existence of any other abnormality which might cause impairment, but judged not to be the cause of dementia. (2) Time interval between development of motor and cognitive symptoms not known. Must also have none of Group IV symptoms present: (1) Cognitive and behavioral symptoms appear solely in the context of other conditions such as acute confusion caused by systemic diseases or abnormalities, drug intoxication, or major depression according to DSM IV. (2) Features compatible with Probable Vascular Dementia criteria accordingly to NINDS-AIREN.
Exclusion criteria
* Subjects with contra-indications to MR imaging and/or tDCS, including pacemakers or claustrophobia * Evidence of large vessel stroke or mass lesion on MRI * Use of anti-cholinergic or neuroleptic drugs * Evidence of atypical parkinsonism on neurological exam * Major psychiatric illness, such as bipolar disorder * Neurological conditions such as epilepsy, stroke, multiple sclerosis, or moderate to severe brain injury * Sensory impairments that significantly limit one's ability to see or hear * A significant history of recent alcohol or drug dependence * Previous major radiation exposure * Pregnancy
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Dementia Cognitive Fluctuations Scale | Baseline and Post-Testing (3-4 weeks) | Score on a 4-item subscale of the 17-item Dementia Cognitive Fluctuation Scale (DCFS), developed to address limitations in prior scales and has good test-retest and inter-rater reliability; this subscale highly discriminates between dementia with Lewy bodies (DLB) and other dementia groups. The DCFS is a subjective report of cognitive fluctuation, the spontaneous change in cognitive ability which is a core diagnostic feature of DLB. Total subscale scores range from 4 to 20, with higher scores indicating greater cognitive fluctuations. A decrease in score between Baseline and Post-Testing indicates an improvement in cognitive fluctuation. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Resting State fMRI | Baseline and Post-Testing (3-4 weeks) | Functional connectivity measures whether activity in different brain regions show similar patterns of change over time. Graph theory metrics of resting-state fMRI can characterize functional connectivity among nodes (regions) of a brain network, and well as between nodes of different brain networks. Network segregation is the difference of within-network and between-network connectivity as a proportion of within-network connectivity, such that higher numbers reflect more segregation. Given that network segregation typically decreases with normal and pathological aging, higher network segregation is generally considered cognitively beneficial. Network segregation was examined for the ventral attention network (the actual focus of stimulation based on observed cholinergic denervation) and the original cingulo-opercular network, which was predicted at the time of grant proposal (but not supported by the observed cholinergic denervation). |
| Stroop Color Word Interference Test - Cognitive Control Performance | Baseline, 3-4 weeks | Outcome Measure Description: Interference score in time to complete the Color Word Interference Test version of the Stroop task from the Delis-Kaplan Executive Function System. Participants 1) identify a series of colors, 2) read color words (e.g. blue) all written in black ink, and 3) name the ink color of color words printed in incongruous colored inks (e.g. for the word green written in red ink, the correct response is red). Tasks are performed as quickly as possible. Time to complete each task is recorded. Interference score is calculated as the time to complete the color-word (interference) test (CWT), less the average of the time to complete the color task (CT) and word-reading task (WT): CWT - ((CT + WT)/2). The score has a theoretical valid range of 0 - 300; a lower score suggests better cognitive control. A negative change (decrease) in score between Baseline and Post-Testing indicates improvement in cognitive control performance. |
| Objective Measures of Working Memory (N-back Test) | Baseline, 3-4 weeks | The n-back test is a working memory task where a participant identify a stimulus that matches the stimulus experienced n steps back. Participants performed a 2-back test, in which they were asked to remember and press a button when presented with a stimulus that appeared two steps before the current one (e.g. square, circle, square). The number of correct and incorrect identifications are normalized (z-score). Total score is the z-score of correct button presses minus the z-score of incorrect button presses. Possible scores range from -4.85 to 4.85. A higher score (d') reflects better discrimination between target and non-target stimuli, and therefore better working memory performance. A positive change (increase) in 2-back score (d') between Baseline and Post-Testing indicates an improvement in working memory performance. |
Countries
United States
Participant flow
Recruitment details
Participants enrolled are those who consented to be in the study. They then underwent a screening process. Three participants did not continue after the screening process.
Participants by arm
| Arm | Count |
|---|---|
| Experimental: HD-tDCS Maximum 4 milliAmp (mA) per channel of HD-tDCS treatment for 20 minutes, for 10 sessions. Total mA dose determined by individualized computational models.
HD-tDCS: Participants will receive HD-tDCS at up to 4 mA per channel for 20 minutes for 10 sessions. Dose determined through individualized computational models. | 13 |
| Total | 13 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 1 |
| Overall Study | Did not pass screening after consenting to participate | 1 |
| Overall Study | Withdrawal by Subject | 1 |
Baseline characteristics
| Characteristic | Experimental: HD-tDCS |
|---|---|
| Age, Continuous | 75.77 years STANDARD_DEVIATION 5.75 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 13 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 13 Participants |
| Region of Enrollment United States | 13 participants |
| Sex: Female, Male Female | 2 Participants |
| Sex: Female, Male Male | 11 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 13 |
| other Total, other adverse events | 13 / 13 |
| serious Total, serious adverse events | 0 / 13 |
Outcome results
Dementia Cognitive Fluctuations Scale
Score on a 4-item subscale of the 17-item Dementia Cognitive Fluctuation Scale (DCFS), developed to address limitations in prior scales and has good test-retest and inter-rater reliability; this subscale highly discriminates between dementia with Lewy bodies (DLB) and other dementia groups. The DCFS is a subjective report of cognitive fluctuation, the spontaneous change in cognitive ability which is a core diagnostic feature of DLB. Total subscale scores range from 4 to 20, with higher scores indicating greater cognitive fluctuations. A decrease in score between Baseline and Post-Testing indicates an improvement in cognitive fluctuation.
Time frame: Baseline and Post-Testing (3-4 weeks)
Population: Data is reported for participants who completed both baseline and week 3/4 measures.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Experimental: HD-tDCS | Dementia Cognitive Fluctuations Scale | Baseline | 11.75 score on a scale | Standard Deviation 3.31 |
| Experimental: HD-tDCS | Dementia Cognitive Fluctuations Scale | Week 3/4 | 8.33 score on a scale | Standard Deviation 1.56 |
Objective Measures of Working Memory (N-back Test)
The n-back test is a working memory task where a participant identify a stimulus that matches the stimulus experienced n steps back. Participants performed a 2-back test, in which they were asked to remember and press a button when presented with a stimulus that appeared two steps before the current one (e.g. square, circle, square). The number of correct and incorrect identifications are normalized (z-score). Total score is the z-score of correct button presses minus the z-score of incorrect button presses. Possible scores range from -4.85 to 4.85. A higher score (d') reflects better discrimination between target and non-target stimuli, and therefore better working memory performance. A positive change (increase) in 2-back score (d') between Baseline and Post-Testing indicates an improvement in working memory performance.
Time frame: Baseline, 3-4 weeks
Population: 12 participants completed the n-back working memory task at both Baseline and Post-Testing, however one participant used an incorrect button to make responses at Baseline, so these responses were not recorded, leaving 11 participants with recorded data at Baseline and Post-Testing. Of these 11, 5 performed below chance (\<50% hit rate) on the control task at one or both timepoints and were excluded from analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Experimental: HD-tDCS | Objective Measures of Working Memory (N-back Test) | Baseline | 0.94 calculated score | Standard Deviation 0.72 |
| Experimental: HD-tDCS | Objective Measures of Working Memory (N-back Test) | 3-4 weeks | 1.24 calculated score | Standard Deviation 0.6 |
Resting State fMRI
Functional connectivity measures whether activity in different brain regions show similar patterns of change over time. Graph theory metrics of resting-state fMRI can characterize functional connectivity among nodes (regions) of a brain network, and well as between nodes of different brain networks. Network segregation is the difference of within-network and between-network connectivity as a proportion of within-network connectivity, such that higher numbers reflect more segregation. Given that network segregation typically decreases with normal and pathological aging, higher network segregation is generally considered cognitively beneficial. Network segregation was examined for the ventral attention network (the actual focus of stimulation based on observed cholinergic denervation) and the original cingulo-opercular network, which was predicted at the time of grant proposal (but not supported by the observed cholinergic denervation).
Time frame: Baseline and Post-Testing (3-4 weeks)
Population: Ten participants completed resting-State fMRI at Baseline and Post-Testing. Two participants were not eligible for MRI.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Experimental: HD-tDCS | Resting State fMRI | Baseline - Ventral Attention Network | 0.23 ratio of network segregation | Standard Deviation 0.17 |
| Experimental: HD-tDCS | Resting State fMRI | 3/4 weeks - Ventral Attention Network | 0.33 ratio of network segregation | Standard Deviation 0.1 |
| Experimental: HD-tDCS | Resting State fMRI | Baseline - Cingulo-opercular network | 0.53 ratio of network segregation | Standard Deviation 0.11 |
| Experimental: HD-tDCS | Resting State fMRI | 3/4 weeks - Cingulo-opercular network | 0.53 ratio of network segregation | Standard Deviation 0.11 |
Stroop Color Word Interference Test - Cognitive Control Performance
Outcome Measure Description: Interference score in time to complete the Color Word Interference Test version of the Stroop task from the Delis-Kaplan Executive Function System. Participants 1) identify a series of colors, 2) read color words (e.g. blue) all written in black ink, and 3) name the ink color of color words printed in incongruous colored inks (e.g. for the word green written in red ink, the correct response is red). Tasks are performed as quickly as possible. Time to complete each task is recorded. Interference score is calculated as the time to complete the color-word (interference) test (CWT), less the average of the time to complete the color task (CT) and word-reading task (WT): CWT - ((CT + WT)/2). The score has a theoretical valid range of 0 - 300; a lower score suggests better cognitive control. A negative change (decrease) in score between Baseline and Post-Testing indicates improvement in cognitive control performance.
Time frame: Baseline, 3-4 weeks
Population: 8 participants completed the Color Word Interference Test at Baseline and Post-Testing. 4 participants did not complete the test. Negative scores are technically possible, but given the known robust and reliable cognitive effort required in color word interference, a negative interference score would call into question the validity of the administration and be excluded. No participants' scores were negative and therefore none were excluded for this reason..
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Experimental: HD-tDCS | Stroop Color Word Interference Test - Cognitive Control Performance | Baseline | 143.44 calculated score | Standard Deviation 51.89 |
| Experimental: HD-tDCS | Stroop Color Word Interference Test - Cognitive Control Performance | 3-4 weeks | 125.15 calculated score | Standard Deviation 52.91 |