Leveraging the Neural Circuits of Hyper-Memory to Ameliorate Memory Dysfunction in Prodromal Alzheimer's Disease (pAD) - Noninvasive Brain Stimulation for pAD (pADmemory)
试验速览
- 阶段
- 不适用
- 状态
- 进行中（未招募）
- 发起方
- 入组人数
- 40
- 试验地点
- 2
- 主要终点
- TMS evoked potentials - TEPs changes. Analysis of cortical excitability and inhibition changes
研究概览
简要总结
Episodic memory refers to the conscious recalling of a personal experience and includes information of an event and the context in which the event took place.
This function is the first to be impaired in Alzheimer's disease, a degenerative condition in which pathological changes are found initially in the medial temporal cortex and then spread in the rest of the cortex starting from post-Rolandic areas.
This study aims at examining the mechanisms that enhance memory processes, based on the information acquired by studying hypermnesic subjects. The recent discovery of subjects with an extraordinary ability to remember past events (highly above-average autobiographical memory) and the development of techniques to manipulate memory circuits in rodents provide a unique opportunity to study the mechanisms that determine the facilitation of memories.
As part of a multicenter project funded by the Ministry of Health in collaboration with La Sapienza University of Rome, the University of Perugia and the Santa Lucia Rehabilitation Center in Rome, the aspect of the project carried out at CIMeC (University of Trento) will consist in evaluating the changes induced by rTMS in patients with prodromal Alzheimer's disease, after stimulation of the regions that appear particularly active in hypermnesic subjects.
This project would offer the possibility of accessing an innovative non-invasive, and non-pharmacological treatment.
The specific objectives are:
(i) To evaluate the effectiveness of rTMS applied to hyperactive areas in hypermnesic subjects in enhancing autobiographical memories; (ii) Analyzing the neural correlates of the behavioral variations. The study will allow us to define whether it is possible to improve the recollection of autobiographical events by stimulating the circuits that are more active in hypermnesic subjects.
The results will be crucial to gain a better understanding of the mechanisms through which brain stimulation contributes to the promotion of neuroplasticity and the effects of rTMS in the prodromal stages of Alzheimer's dementia.
详细描述
METHODS AND PROCEDURES:
Materials and methods of the investigation will be the following:
- repetitive Transcranial Magnetic Stimulation (rTMS)
- A general neuropsychological assessment battery
- Questionnaires and scales
- Electroencephalogram (EEG) recording
- Combined EEG recording and single-pulse TMS (TMS- EEG)
Different rTMS stimulation protocols will be applied:
- rTMS: this protocol consists in the administration of 1600 pulses at 20 Hz, alternating 2 s of stimulation and 28 seconds of pause. rTMS will be applied over the left dorsolateral prefrontal cortex (left DLPFC). The coil will be placed at the EEG 10-20 International System position of the F3 electrode. The stimulation intensity will be equal to 100% of the motor threshold value at rest. rTMS will be delivered through a Medtronic-Magpro magnetic stimulator and a 70-mm figure-of-eight coil.
- sham rTMS: as for the protocol that involves the application of sham/placebo stimulation, the rTMS will be administered by applying to the coil a piece of wood or plastic of about 30 mm in thickness, a distance that ensures that the magnetic pulse does not reach the cortex and built so to appear as an integral part of the apparatus.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Factorial
- 主要目的
- Basic Science
- 盲法
- Triple (Participant, Care Provider, Outcomes Assessor)
盲法说明
Triple (Participant, Care Provider, Outcomes Assessor) We will implement a randomized, non-pharmacological study, with a double-blind certified medical device (neither the patient nor the clinician / researcher who will carry out the evaluations will be aware of the group to which the patient has been assigned).
入排标准
- 年龄范围
- 50 Years 至 85 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •right-handed
- •meet inclusion criteria related to TMS (attached in the protocol)
- •to be able to provide information regarding their cognitive and functional skills, or have a caregiver available who is able to provide the patient information necessary for participation in the study and who is present when signing the patient's informed consent.
- •pAD Patient Inclusion Criteria:
- •Clinical Dementia Rating Scale <2;
- •Diagnosis of prodromal Alzheimer's disease (amnesic MCI) according to the diagnostic criteria;
- •Neurodegeneration biomarker for AD (FDG-PET or CSF), diagnosis confirmed by clinical follow-up;
- •Montreal Cognitive Assessment (MoCA) test overall score within the normal limits (equivalent score of 1);
- •Absence of severe vascular distress; Patients will be selected through clinical evaluation (battery of neuropsychological tests at the Neurocognitive Rehabilitation Center - CeRiN)
排除标准
- •Patients who are unable to perform the tasks required by the experimental procedure;
- •History and/or evidence of any other central nervous system disorder that could be interpreted as a cause of dementia such as structural or developmental abnormality, infectious epilepsy, degenerative or inflammatory/demyelinating diseases of the central nervous system such as Parkinson's disease;
- •History of significant psychiatric disease which, in the investigator's judgment, could interfere with study participation.
- •History of alcohol or other substance abuse, according to DSM-V criteria, if this could be a contributing factor to dementia;
- •Presence of cardiac pacemakers, electronic prostheses, bio-stimulators, metal inserts, or electrodes implanted in the brain or skull, or spine;
- •Inability to read and /or understand the written information;
- •Dermatitis, eczema, extensive scars on the scalp
- •Absolute exclusion criteria (criteria for TMS)
- •presence of cardiac pacemakers, artificial heart valves and/or bio- stimulators;
- •presence of hearing aids located in the middle ear;
- •presence of metal inserts on the head and shoulders;
结局指标
主要结局
TMS evoked potentials - TEPs changes. Analysis of cortical excitability and inhibition changes
时间窗: Prior to treatment (baseline=t0=week 1), at the end of the 10 days rTMS phase (t1=Week 4), 3 months post-treatment (t2=Week 16)
180 pulses will be delivered to the target area (left DLPFC) during EEG registration. This outcome will analyze cortical excitability and inhibition changes induced in the state of excitability/inhibition of brain circuits following the TMS impulse. The amplitude will be used as a marker of cortical excitability.
Connectivity Index, cortico-cortical connectivity analysis: changes in the connectivity evoked by TMS
时间窗: Prior to treatment (baseline=t0=week 1), at the end of the 10 days rTMS phase (t1=Week 4), 3 months post-treatment (t2=Week 16)
180 pulses will be delivered to the target area (left DLPFC) during EEG registration. This outcome will analyze changes in the latencies and topographical distribution of the TEPs thus providing a connectivity index. This connectivity index will be used to infer the propagation of the activity from the stimulation site to functionally connected areas.
TMS evoked oscillations changes
时间窗: Prior to treatment (baseline=t0=week 1), at the end of the 10 days rTMS phase (t1=Week 4), 3 months post-treatment (t2=Week 16)
180 pulses will be delivered to the target area (left DLPFC) during EEG registration. This outcome will analyze changes in responses induced by TMS in the frequency domain for the intrinsic capacity of the stimulated area to generate oscillatory activity in specific frequency bands
Autobiographical Memory Interview: change in performance
时间窗: Prior to treatment (baseline=t0=week 1), at the end of the 10 days rTMS phase (t1=Week 4), 3 months post-treatment (t2=Week 16), & 6 months post treatment (t3=Week 28)]
The Autobiographical Memory Interview is a method of assessing autobiographical memory using a text-based analysis of transcribed autobiographical protocols. The script is segmented into internal (temporally and contextually specific) details and external (generic or semantic) details, which are then tallied. Internal scores are conceptualized as reflecting the episodic richness of the mental simulation, whereas external scores include non-episodic components of the mental simulation such as generic information, routine simulations, or verbal artifacts like repetitions. Mean changes on test scores: \[score ranges min=N/A, max= no limit, higher score=better outcome\]
Free and Cued Selective Recall Reminding Test - episodic memory: change in performance
时间窗: Prior to treatment (baseline=t0=week 1), at the end of the 10 days rTMS phase (t1=Week 4), 3 months post-treatment (t2=Week 16), & 6 months post treatment (t3=Week 28)]
Free and Cued Selective Recall Reminding Test: the three measures being evaluated include free recall (the cumulative sum of free recall from the trials; range 0-48), total recall (the cumulative sum of free recall + cued recall from the trials, range 0-48), and cue efficiency (total recall-free recall)/(48-free recall, range 0.0-1.0). Mean changes on test scores: \[higher score=better outcome\]
Montreal Cognitive Assessment Test - cognitive screening: change in performance
时间窗: Prior to treatment (baseline=t0=week 1), at the end of the 10 days rTMS phase (t1=Week 4), 3 months post-treatment (t2=Week 16), & 6 months post treatment (t3=Week 28)]
Scores on the Montreal Cognitive Assessment Test range from zero to 30. A score of 26 and higher is considered normal. If the score is below 25, the result indicates a possible cognitive impairment. Mean changes in test scores: \[higher score=better outcome\]
次要结局
- Raven's Coloured Progressive Matrices™: change in performance(Prior to treatment (baseline=t0=week 1), at the end of the 10 days rTMS phase (t1=Week 4), 3 months post-treatment (t2=Week 16), & 6 months post treatment (t3=Week 28)])
- Forward Digit Span and Reverse Digit Span: change in performance(Prior to treatment (baseline=t0=week 1), at the end of the 10 days rTMS phase (t1=Week 4), 3 months post-treatment (t2=Week 16), & 6 months post treatment (t3=Week 28)])
- Spatial Span: change in performance(Prior to treatment (baseline=t0=week 1), at the end of the 10 days rTMS phase (t1=Week 4), 3 months post-treatment (t2=Week 16), & 6 months post treatment (t3=Week 28)])
- Prose Memory: change in performance(Prior to treatment (baseline=t0=week 1), at the end of the 10 days rTMS phase (t1=Week 4), 3 months post-treatment (t2=Week 16), & 6 months post treatment (t3=Week 28)])
- Free And Cued Selective Reminding Test: change in performance(Prior to treatment (baseline=t0=week 1), at the end of the 10 days rTMS phase (t1=Week 4), 3 months post-treatment (t2=Week 16), & 6 months post treatment (t3=Week 28)])
- Token Test: change in performance(Prior to treatment (baseline=t0=week 1), at the end of the intensive treatment phase (t1=Week 4), 3 months post-treatment (t2=Week 16), & 6 months post treatment (t4=Week 28)])
- Verbal fluency - Semantic fluency and Phonemic fluency: change in performance(Prior to treatment (baseline=t0=week 1), at the end of the 10 days rTMS phase (t1=Week 4), 3 months post-treatment (t2=Week 16), & 6 months post treatment (t3=Week 28)])
- Multiple Features Cancellation task: change in performance(Prior to treatment (baseline=t0=week 1), at the end of the 10 days rTMS phase (t1=Week 4), 3 months post-treatment (t2=Week 16), & 6 months post treatment (t3=Week 28)])
- Trail Making test (for A, B and B-A conditions): change in performance(Prior to treatment (baseline=t0=week 1), at the end of the 10 days rTMS phase (t1=Week 4), 3 months post-treatment (t2=Week 16), & 6 months post treatment (t3=Week 28)])
- Rey-Osterrieth Complex Figure and modified Taylor complex figures: change in performance(Prior to treatment (baseline=t0=week 1), at the end of the 10 days rTMS phase (t1=Week 4), 3 months post-treatment (t2=Week 16), & 6 months post treatment (t3=Week 28)])
- The Stroop Color and Word Test: change in performance(Prior to treatment (baseline=t0=week 1), at the end of the 10 days rTMS phase (t1=Week 4), 3 months post-treatment (t2=Week 16), & 6 months post treatment (t3=Week 28)])
- Attentional Matrices: change in performance(Prior to treatment (baseline=t0=week 1), at the end of the 10 days rTMS phase (t1=Week 4), 3 months post-treatment (t2=Week 16), & 6 months post treatment (t3=Week 28)])