Aging, Alzheimer Disease, Mild Cognitive Impairment
Conditions
Brief summary
Normal aging is associated with a progressive decline in cognitive functions, especially memory. This decline in cognitive function can negatively impact the quality of life of older adults. Although there are currently few possibilities to prevent and/or slow the signs of cognitive decline, both those associated with age and neurodegenerative pathologies, one of the non-invasive brain stimulation techniques that has gained attention in recent years is Transcranial Direct Current Stimulation (tDCS). tDCS is a technique based on the application of a low-intensity (\< 2 mA) direct electrical current between two large-area electrodes placed on various surface areas of the head. Moreover, according to safety-related meta-analyses it is a very safe technique, without any major side effects, provided that internationally established safety protocols are taken into account in its application. This technique has recently been investigated as a potential treatment for both healthy elderly people and people with mild cognitive impairment and Alzheimer's disease in several cognitive variables, having shown encouraging results in working memory learning curves, modulation of plasticity and recognition tasks. This project aims to implement an intervention using transcranial direct current stimulation in healthy older adults, MCI and AD. The main objective is to test if there is an improvement in cognitive efficiency and if the changes are maintained over time (1 month). For this purpose, the effect of the technique will be studied on participants assigned to treatment and control groups, analyzing the possible modifications in the following cognitive variables: cognitive plasticity and learning potential, recognition and familiarity and false alarms.
Detailed description
The clinical trial protocol involves the recruitment of participants from three different groups: healthy older adults, individuals with mild cognitive impairment (MCI), and patients with Alzheimer's disease (AD). Participants will be randomly assigned to either a treatment group or a control group. For the treatment group, transcranial direct current stimulation (tDCS) will be administered over a specified period using a standard protocol involving the application of low-intensity electrical current (\< 2 mA) through electrodes placed on specific scalp areas. The duration and frequency of stimulation will be predetermined based on scientific literature and established safety recommendations. The control group will receive a sham procedure where a low-intensity current, having no effect on neuronal activity, will be applied to maintain treatment masking. Prior to commencing the intervention, a baseline assessment of participants' cognitive functions will be conducted using a battery of standardized tests, including measures of cognitive plasticity, memory, attention, executive functions, and other relevant cognitive abilities. During the intervention period, regular tDCS or placebo sessions will be conducted according to participants' assigned groups. Additionally, data on potential side effects and tolerability of the technique will be collected. At the end of the intervention period, a post-treatment assessment will be conducted to determine any changes in participants' cognitive functions. These data will be compared to baseline assessments to ascertain the intervention's efficacy. Furthermore, participants will be followed up for a period of at least one month after the intervention to evaluate the persistence of effects and any potential long-term effects. It is important to emphasize that this protocol will adhere to all ethical and safety regulations established by relevant regulatory authorities and ethics committees. Participants will be fully informed about the procedures and risks involved, and their informed consent will be obtained before their participation in the study.
Interventions
DEVICETranscranial direct current stimulation (tDCS)
10 sessions of tDCS stimulation on dorsolateral prefrontal cortex with the apparatus HDC stimulator (Newronika TM)
DEVICESham stimulation
The sham group received direct current only on the ramps to generate a sensation of the effect.10 sessions
Sponsors
University of Valencia
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Subject)
Intervention model description
sham versus stimulation
Eligibility
Sex/Gender
ALL
Age
65 Years to No maximum
Healthy volunteers
Yes
Inclusion criteria
For the group of healthy older adults: * MEC score greater than 26 points. * GDS between 1 and 3. For the MCI group: * MEC score between 21 and 26 points. * GDS between 1 and 3. For the mild EA group: * MEC score between 18 and 23 points. * GDS between 3 and 4.
Exclusion criteria
* Presentation of contraindications to tDCS (presence of intracranial metal implants, intracranial hypertension, comitial risk). * Significant asymptomatic neurovascular disease * History of previous symptomatic stroke * Alcohol or drug abuse/dependence * Severe psychiatric symptoms * Depressive symptoms higher than mild
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Complutense Verbal Learning Test (TAVEC) - Memory | Baseline to approximately 4 weeks | This test presents a list of 16 words that, after being read by the evaluator, have to be repeated by the participant. The list is repeated five times (trials); the participant is again asked to remember the 16 words. The test was administered to evaluate the participant's immediate memory (Trial 1), learning ability (Trial 5 ). Post-intervention minus baseline. Scale is scored 0-16. Difference score range is (-16 to 16) with positive scores reflecting improvement. |
| Mini Mental State Examination | Baseline to approximately 4 weeks | This is a screening test for general cognitive status. This test is evaluated on a maximum of 30 points. Participants with scores equal to or below 23 would be considered cognitively deficient. Post-intervention minus baseline. Scale is scored 0-30. Difference score range is (-30 to 30) with positive scores reflecting improvement. |
| Digits Wechsler Intelligence Scale for Adults-III (WAIS-III) | Baseline to approximately 4 weeks | Direct and inverse digits of the Wechsler Intelligence Scale for Adults-III (Wechsler, 2001). These tests assess attentional capacity by exposing the participant to increasing amounts of information. On the direct digits task, which is used to assess immediate recall, the subject must repeat the sequence of numbers in the same order in which they are read by the examiner. On the inverse digit task, which assesses working memory and mental flexibility, the subject must say the digits backwards from the way they were presented by the examiner. Both tests are evaluated in the same way, assigning one point for each correct item, with a maximum score of 16 for both tests. Post-intervention minus baseline. Difference score range is (-16 to 16) with positive scores reflecting improvement. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Barcelona Test (BT) - Ability to Access and Recall Elements From the Lexical and Semantic Store | Baseline to approximately 4 weeks | Barcelona Test assesses the ability to access and recall lexical and semantic items by means of two subtests: a. Semantic fluency: recall the highest number of words from the category 'animals' in one minute; b. Phonological fluency: recall the highest number of words beginning with the letter 'p' in three minutes. Minimum and maximum range for Semantic fluency and Phonological fluency: 0 to n (no upper limit). Method of calculation: Scores for each subtest are reported separately. No combined scores or averages between subtests are calculated. Interpretation: Good categorical recall is considered good when evoking more than 16 animals in 1 minute and good verbal fluency when evoking more than 19 words beginning with 'p' in 3 minutes. This test assesses the ability to access and recall items from the lexical and semantic store. Processes involved: processing speed, cognitive flexibility and working memory. Post-intervention less baseline with positive scores reflecting improvement. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Global Deterioration Scale (GDS) | Baseline to approximately 4 weeks | This test is evaluated on a maximum of 30 points. Participants with scores equal to or below 23 would be considered cognitively deficient. |
| Experimental Task - Recognition Familiarity and False Alarms | Baseline to approximately 4 weeks | This experimental task is composed by three lists of words with two conditions: half and entire. The half condition included two lists of 50 words each, formed entirely from the following letters of the Spanish alphabet: a, e, u, b, d, g, j, n, r, and z (list A) or i, o, c, f, h, l, m, p, s, t, v, and y (list B). List C (entire condition) contained 50 words formed from the entire alphabet, with the only criterion being that each word had to contain at least one letter from list A and at least one letter from list B. In the half condition, the recognition estimates for each participant were derived by subtracting the proportion of false alarms on words with the same letters, as in the study list, from the proportion of hits, whereas in the entire condition, the recognition estimates were derived by subtracting the proportion of false alarms on words with all the letters in the alphabet from the proportion of hits as a way to control the response bias of the participants. |
| Memory Alteration Test (M@T) - Cognitive Impairment | Baseline to approximately 4 weeks | This test offers a rapid and effective screening with excellent discriminative properties for amnestic Mild Cognitive Impairment (MCI-A) and early AD in the general primary care population. The test assesses a variety of abilities such as encoding, orientation, semantic memory and free recall. It consists of oral questions with only one possible answer, and the maximum achievable score is 50 points. The optimal cut-off point for distinguishing amnestic-like mild cognitive impairment from subjective memory complaints is 37 points. The optimal cut-off point for Alzheimer's disease is 31 points. Post-intervention minus baseline. Scale is scored 0-50. Difference score range is (-50 to 50) with positive scores reflecting improvement. |
Countries
Spain
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| tDCS. Transcranial Direct Current Stimulation The stimulation time was 20 minutes, with an initial and final ramp of 30 seconds so that the participant could adapt to the sensation of the current. 10 sesions. Constant current intensity of 2 mA The anode was placed on position F3, coinciding with the dorsolateral prefrontal cortex, and the cathode was placed on Fp2, coinciding with the right supraorbital area (rSO).
Transcranial direct current stimulation (tDCS): 10 sessions of tDCS stimulation on dorsolateral prefrontal cortex with the apparatus HDC stimulator (Newronika TM) | 17 |
| Sham Stimulation The sham group received direct current only on the ramps to generate a sensation of the effect.
Sham stimulation: The sham group received direct current only on the ramps to generate a sensation of the effect.10 sessions | 16 |
| Total | 33 |
Baseline characteristics
| Characteristic | Sham Stimulation | Total | tDCS. Transcranial Direct Current Stimulation |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 16 Participants | 33 Participants | 17 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Continuous | 73.4 years STANDARD_DEVIATION 6.2 | 75 years STANDARD_DEVIATION 6.08 | 76.6 years STANDARD_DEVIATION 5.7 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 16 Participants | 33 Participants | 17 Participants |
| Region of Enrollment Spain | 16 participants | 33 participants | 17 participants |
| Sex: Female, Male Female | 8 Participants | 17 Participants | 9 Participants |
| Sex: Female, Male Male | 8 Participants | 16 Participants | 8 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 17 | 0 / 16 |
| other Total, other adverse events | 0 / 17 | 0 / 16 |
| serious Total, serious adverse events | 0 / 17 | 0 / 16 |
Outcome results
Primary
Complutense Verbal Learning Test (TAVEC) - Memory
This test presents a list of 16 words that, after being read by the evaluator, have to be repeated by the participant. The list is repeated five times (trials); the participant is again asked to remember the 16 words. The test was administered to evaluate the participant's immediate memory (Trial 1), learning ability (Trial 5 ). Post-intervention minus baseline. Scale is scored 0-16. Difference score range is (-16 to 16) with positive scores reflecting improvement.
Time frame: Baseline to approximately 4 weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| tDCS. Transcranial Direct Current Stimulation | Complutense Verbal Learning Test (TAVEC) - Memory | Trial 1 | 0.94 units on a scale | Standard Deviation 0.35 |
| tDCS. Transcranial Direct Current Stimulation | Complutense Verbal Learning Test (TAVEC) - Memory | Trial 5 | 1.65 units on a scale | Standard Deviation 0.5 |
| Sham Stimulation | Complutense Verbal Learning Test (TAVEC) - Memory | Trial 5 | -0.31 units on a scale | Standard Deviation 0.4 |
| Sham Stimulation | Complutense Verbal Learning Test (TAVEC) - Memory | Trial 1 | -0.81 units on a scale | Standard Deviation 0.03 |
Primary
Digits Wechsler Intelligence Scale for Adults-III (WAIS-III)
Direct and inverse digits of the Wechsler Intelligence Scale for Adults-III (Wechsler, 2001). These tests assess attentional capacity by exposing the participant to increasing amounts of information. On the direct digits task, which is used to assess immediate recall, the subject must repeat the sequence of numbers in the same order in which they are read by the examiner. On the inverse digit task, which assesses working memory and mental flexibility, the subject must say the digits backwards from the way they were presented by the examiner. Both tests are evaluated in the same way, assigning one point for each correct item, with a maximum score of 16 for both tests. Post-intervention minus baseline. Difference score range is (-16 to 16) with positive scores reflecting improvement.
Time frame: Baseline to approximately 4 weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| tDCS. Transcranial Direct Current Stimulation | Digits Wechsler Intelligence Scale for Adults-III (WAIS-III) | Direct Digits | 1.35 units on a scale | Standard Deviation 0.62 |
| tDCS. Transcranial Direct Current Stimulation | Digits Wechsler Intelligence Scale for Adults-III (WAIS-III) | Inverse digits | 0.17 units on a scale | Standard Deviation 1.15 |
| Sham Stimulation | Digits Wechsler Intelligence Scale for Adults-III (WAIS-III) | Direct Digits | -0.18 units on a scale | Standard Deviation 0.84 |
| Sham Stimulation | Digits Wechsler Intelligence Scale for Adults-III (WAIS-III) | Inverse digits | -0.43 units on a scale | Standard Deviation 0.05 |
Primary
Mini Mental State Examination
This is a screening test for general cognitive status. This test is evaluated on a maximum of 30 points. Participants with scores equal to or below 23 would be considered cognitively deficient. Post-intervention minus baseline. Scale is scored 0-30. Difference score range is (-30 to 30) with positive scores reflecting improvement.
Time frame: Baseline to approximately 4 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| tDCS. Transcranial Direct Current Stimulation | Mini Mental State Examination | 2.18 score on a scale | Standard Deviation 0.03 |
| Sham Stimulation | Mini Mental State Examination | -0.44 score on a scale | Standard Deviation 1.28 |
Secondary
Barcelona Test (BT) - Ability to Access and Recall Elements From the Lexical and Semantic Store
Barcelona Test assesses the ability to access and recall lexical and semantic items by means of two subtests: a. Semantic fluency: recall the highest number of words from the category 'animals' in one minute; b. Phonological fluency: recall the highest number of words beginning with the letter 'p' in three minutes. Minimum and maximum range for Semantic fluency and Phonological fluency: 0 to n (no upper limit). Method of calculation: Scores for each subtest are reported separately. No combined scores or averages between subtests are calculated. Interpretation: Good categorical recall is considered good when evoking more than 16 animals in 1 minute and good verbal fluency when evoking more than 19 words beginning with 'p' in 3 minutes. This test assesses the ability to access and recall items from the lexical and semantic store. Processes involved: processing speed, cognitive flexibility and working memory. Post-intervention less baseline with positive scores reflecting improvement.
Time frame: Baseline to approximately 4 weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| tDCS. Transcranial Direct Current Stimulation | Barcelona Test (BT) - Ability to Access and Recall Elements From the Lexical and Semantic Store | Semantic fluency | 0.47 Number of words evoked | Standard Deviation 4.47 |
| tDCS. Transcranial Direct Current Stimulation | Barcelona Test (BT) - Ability to Access and Recall Elements From the Lexical and Semantic Store | Phonological fluency | 1.77 Number of words evoked | Standard Deviation 0.1 |
| Sham Stimulation | Barcelona Test (BT) - Ability to Access and Recall Elements From the Lexical and Semantic Store | Semantic fluency | -5.72 Number of words evoked | Standard Deviation 4.22 |
| Sham Stimulation | Barcelona Test (BT) - Ability to Access and Recall Elements From the Lexical and Semantic Store | Phonological fluency | 0.69 Number of words evoked | Standard Deviation 0.46 |
Other Pre-specified
Experimental Task - Recognition Familiarity and False Alarms
This experimental task is composed by three lists of words with two conditions: half and entire. The half condition included two lists of 50 words each, formed entirely from the following letters of the Spanish alphabet: a, e, u, b, d, g, j, n, r, and z (list A) or i, o, c, f, h, l, m, p, s, t, v, and y (list B). List C (entire condition) contained 50 words formed from the entire alphabet, with the only criterion being that each word had to contain at least one letter from list A and at least one letter from list B. In the half condition, the recognition estimates for each participant were derived by subtracting the proportion of false alarms on words with the same letters, as in the study list, from the proportion of hits, whereas in the entire condition, the recognition estimates were derived by subtracting the proportion of false alarms on words with all the letters in the alphabet from the proportion of hits as a way to control the response bias of the participants.
Time frame: Baseline to approximately 4 weeks
Other Pre-specified
Global Deterioration Scale (GDS)
This test is evaluated on a maximum of 30 points. Participants with scores equal to or below 23 would be considered cognitively deficient.
Time frame: Baseline to approximately 4 weeks
Other Pre-specified
Memory Alteration Test (M@T) - Cognitive Impairment
This test offers a rapid and effective screening with excellent discriminative properties for amnestic Mild Cognitive Impairment (MCI-A) and early AD in the general primary care population. The test assesses a variety of abilities such as encoding, orientation, semantic memory and free recall. It consists of oral questions with only one possible answer, and the maximum achievable score is 50 points. The optimal cut-off point for distinguishing amnestic-like mild cognitive impairment from subjective memory complaints is 37 points. The optimal cut-off point for Alzheimer's disease is 31 points. Post-intervention minus baseline. Scale is scored 0-50. Difference score range is (-50 to 50) with positive scores reflecting improvement.
Time frame: Baseline to approximately 4 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| tDCS. Transcranial Direct Current Stimulation | Memory Alteration Test (M@T) - Cognitive Impairment | 6.06 score on a scale | Standard Deviation 2.19 |
| Sham Stimulation | Memory Alteration Test (M@T) - Cognitive Impairment | -0.88 score on a scale | Standard Deviation 1.7 |