Novel Personalized Non Invasive Combined Magnetic and Electrical Stimulation of the DMN in Mild AD Patients

Official title

Novel Personalized Non Invasive Combined Magnetic and Electrical Stimulation of the Default Mode Network in Mild AD Patients (CMES-AD)

Overview

Alzheimer's disease (AD) is increasingly recognized as a disorder marked by early synaptic dysfunction and disrupted brain network connectivity, beyond the traditional focus on amyloid pathology. Synaptic plasticity (crucial for learning and memory) is compromised in AD and represents a promising therapeutic target. In particular, alterations in the Default Mode Network (DMN), especially in regions like the precuneus, suggest that restoring connectivity and enhancing plasticity may improve cognitive outcomes. This project proposes a novel, precision-delivered non-invasive brain stimulation protocol that combines repetitive transcranial magnetic stimulation (rTMS) and transcranial alternating current stimulation (tACS) over the DMN. The intervention will be evaluated through cognitive testing, blood-based biomarkers, MRI and TMS-EEG, alongside immersive virtual environments to assess sensorimotor and cognitive function. This approach aims to test neuromodulation strategies capable of slowing neurodegeneration and supporting early detection and rehabilitation in AD.

Detailed description

Patients will be screened at trial sites for determination of eligibility to enter the study on the basis of diagnostic evaluations, according to current diagnostic criteria for probable AD, and safety assessments (vital sign complete physical and neurological examinations). The efficacy assessments (cognitive/behavioral evaluations) will be performed at Baseline before starting treatment and repeated on- treatment at Weeks 0, 12 and 24. Plasma biomarkers will be collected at baseline and at Week 12 and 24. Visit windows are ±7 days for all the scheduled visits. In case a visit is performed outside its window, subsequent visits will be performed in keeping with the original visit schedule. At each in-clinic visit (or upon early termination), AEs will be recorded, at screening, baseline, Week 12 and 24 vital signs measured, and physical and neurological examination performed.

Interventions

• Device Combined iTBS-tACS
  The iTBS-tACS will be applied over the precuneus and last for 190 s, with the tACS electrode positioned on the scalp and the iTBS coil positioned just above it. The iTBS protocol will consist of 600 pulses, delivered in 20 trains of 10 bursts with an interval of 8 seconds between each train. Each burst consists of three pulses at 50Hz, repeated at 5Hz. The total duration will therefore be 190 seconds. iTBS and tACS will be synchronized using a BrainTrigger and SIGNAL Software so that both stimul
• Device iTBS-sham tACS
  The iTBS-tACS will be applied over the precuneus and last for 190 s, with the tACS electrode positioned on the scalp and the iTBS coil positioned just above it. The iTBS protocol will consist of 600 pulses, delivered in 20 trains of 10 bursts with an interval of 8 seconds between each train. Each burst consists of three pulses at 50Hz, repeated at 5Hz. The total duration will therefore be 190 seconds. For the tACS sham condition, the electric current will not be applied, but there will be a 2 s
• Device sham iTBS- sham tACS
  The iTBS-tACS will be applied over the precuneus and last for 190 s, with the tACS electrode positioned on the scalp and the iTBS coil positioned just above it. The iTBS protocol will consist of 600 pulses, delivered in 20 trains of 10 bursts with an interval of 8 seconds between each train. Each burst consists of three pulses at 50Hz, repeated at 5Hz. The total duration will therefore be 190 seconds. For the iTBS sham condition, stimulation was delivered with the coil angled at 90°, with only

Primary outcome measures

• integrated Alzheimer Disease Rating Scale (iADRS) [Time frame: Change from baseline to the end of treatment at week 24.]

Secondary outcome measures (10)

• Change in the Alzheimer's Disease Cooperative Study - Activities of Daily Living (ADCS-ADL) score. [Time frame: Change from baseline to the end of treatment at week 24.]
• Alzheimer Disease Cooperative Study-Instrumental Activities of Daily Living (ADCS-iADL). [Time frame: Change from baseline to week 24.]
• Change in the Clinical Dementia Rating scale Sum of Boxes (CDR-SoB) score. [Time frame: Change from baseline to the end of treatment at week 24.]
• Change in the Alzheimer Disease Assessment Cognitive Scale (ADAS-Cog13) score. [Time frame: Change from baseline to the end of treatment at week 24.]
• Change in the Neuropsychiatric Personal Inventory (NPI) score. [Time frame: Change from baseline to the end of treatment at week 24.]
• Change in the Mini-Mental State Examination (MMSE) score. [Time frame: Change from baseline to the end of treatment at week 24.]
• Change in the Montreal Overall Cognitive Assessment (MoCA) score. [Time frame: Change from baseline to the end of treatment at week 24.]
• Change in Face-Name Association Task (FNAT) score. [Time frame: Change from baseline to the end of treatment at week 24.]
• Change in Apathy Motivation index (AMI) score. [Time frame: Change from baseline to the end of treatment at week 24.]
• Change in the Frontal Assessment Battery (FAB) score. [Time frame: Change from baseline to the end of treatment at week 24.]

Eligibility criteria

Inclusion criteria

• Patients with a diagnosis of AD according to IWG criteria
• 20 > MMSE < 28
• Patients with CSF specific biomarker profile or with a positive Amyloid Pet Scan consistent with the presence of amyloid pathology
• Global Clinical Dementia Rating (CDR) ≤1
• Previous decline in cognition for more than six months as documented in patient medical records
• A caregiver available and living in the same household or interacting with the patient and available
• Patients living at home or nursing home setting without continuous nursing care
• General health status acceptable for a participation in a 6-month clinical trial
• Stable pharmacological treatment for at least one month prior to screening
• No regular intake of prohibited medications.
• Signed informed consent by the patient. If there are any doubts that the patient is mentally capable of giving informed consent, the patient will be examined and verified to be mentally capable by an independent physician/ neurologist, prior to the initiation of any study specific procedure. Signed consent of the caregiver

Exclusion criteria

• Failure to undergo screening or baseline exams
• Hospitalization or change in chronic concomitant medications one month before the screening or during the screening period
• Clinical, laboratory, or neuroimaging results consistent with:

• other primary degenerative dementia (Lewy body dementia, frontotemporal dementia, Huntington's disease, Creutzfeldt-Jakob disease, Down syndrome, etc.);
• other neurodegenerative conditions (Parkinson's disease, amyotrophic lateral sclerosis, etc.);
• orthostatic hypotension and autonomic disorders
• cerebrovascular disease (major infarction, a strategic infarction or multiple lacunar infarctions, extensive white matter lesions > one quarter of total white matter);
• other central nervous system diseases (severe traumatic brain injury, tumors, subdural hematoma, or other space-occupying processes, etc.);
• seizure disorder.
• Other infectious, metabolic, or systemic diseases affecting the central nervous system (syphilis, existing hypothyroidism, current vitamin B12 or folate deficiency, serum electrolytes outside normal limits, juvenile diabetes, etc.).
• A current DSM-V diagnosis of major depression, schizophrenia, or bipolar disorder.
• Clinically significant, advanced, or unstable disease that may interfere with primary or secondary variable assessments and may affect the assessment of the patient's clinical or mental state, or expose the patient to special risk, such as:

• Disability that may prevent the patient from completing all study requirements (e.g., blindness, deafness, severe language difficulties, etc.);
• Opioid-containing analgesics
• Suspected or known drug or alcohol abuse, i.e., more than about 60 g of alcohol (about 1 liter of beer or 500 ml of wine) per day, indicated by a high mean corpuscular volume (MCV) above the normal value at screening;
• Any condition that, in the investigator's judgment, makes the patient unsuitable for inclusion

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Quadruple blind

Primary purpose

Treatment

Study locations

Italy · 2 centers

• IRCCS Santa Lucia Foundation — Rome
• I.R.C.C.S. Centro Neurolesi Bonino Pulejo — Messina

Publications

• Chou HY, Chen SC, Yen TH, Han HM. Effect of a Virtual Reality-Based Exercise Program on Fatigue in Hospitalized Taiwanese End-Stage Renal Disease Patients Undergoing Hemodialysis. Clin Nurs Res. 2020 Jul;29(6):368-374. doi: 10.1177/1054773818788511. Epub 2018 Jul 15. PMID 30009636
• Blennow K, Zetterberg H. Biomarkers for Alzheimer's disease: current status and prospects for the future. J Intern Med. 2018 Dec;284(6):643-663. doi: 10.1111/joim.12816. Epub 2018 Aug 19. PMID 30051512
• Fox MD, Halko MA, Eldaief MC, Pascual-Leone A. Measuring and manipulating brain connectivity with resting state functional connectivity magnetic resonance imaging (fcMRI) and transcranial magnetic stimulation (TMS). Neuroimage. 2012 Oct 1;62(4):2232-43. doi: 10.1016/j.neuroimage.2012.03.035. Epub 2012 Mar 19. PMID 22465297
• Gili T, Cercignani M, Serra L, Perri R, Giove F, Maraviglia B, Caltagirone C, Bozzali M. Regional brain atrophy and functional disconnection across Alzheimer's disease evolution. J Neurol Neurosurg Psychiatry. 2011 Jan;82(1):58-66. doi: 10.1136/jnnp.2009.199935. Epub 2010 Jul 16. PMID 20639384
• Koch G, Casula EP, Bonni S, Borghi I, Assogna M, Minei M, Pellicciari MC, Motta C, D'Acunto A, Porrazzini F, Maiella M, Ferrari C, Caltagirone C, Santarnecchi E, Bozzali M, Martorana A. Precuneus magnetic stimulation for Alzheimer's disease: a randomized, sham-controlled trial. Brain. 2022 Nov 21;145(11):3776-3786. doi: 10.1093/brain/awac285. PMID 36281767
• Koch G, Bonni S, Pellicciari MC, Casula EP, Mancini M, Esposito R, Ponzo V, Picazio S, Di Lorenzo F, Serra L, Motta C, Maiella M, Marra C, Cercignani M, Martorana A, Caltagirone C, Bozzali M. Transcranial magnetic stimulation of the precuneus enhances memory and neural activity in prodromal Alzheimer's disease. Neuroimage. 2018 Apr 1;169:302-311. doi: 10.1016/j.neuroimage.2017.12.048. Epub 2017 De PMID 29277405
• Hu Y, Kirmess KM, Meyer MR, Rabinovici GD, Gatsonis C, Siegel BA, Whitmer RA, Apgar C, Hanna L, Kanekiyo M, Kaplow J, Koyama A, Verbel D, Holubasch MS, Knapik SS, Connor J, Contois JH, Jackson EN, Harpstrite SE, Bateman RJ, Holtzman DM, Verghese PB, Fogelman I, Braunstein JB, Yarasheski KE, West T. Assessment of a Plasma Amyloid Probability Score to Estimate Amyloid Positron Emission Tomography Fi PMID 35446396
• Bonni S, Esposito R, Mencarelli L, Di Lorenzo F, Ricci F, Di Iulio F, Savastano E, Candeo F, De Masi F, Coletta A, Vinci AC, Ferraresi M, Mancini M, Casula EP, Borghi I, Spampinato DA, Maiella M, Cinnera AM, Assogna M, Bruno M, Nocilli M, Ferrara M, Russo M, Tagliamonte NL, Ferrari C, Bertino S, Calabro RS, Maggio MG, De Luca R, Burrascano R, Gjonaj E, Mirabile A, De Pasquale P, d'Avella A, Quarta PMID 42482244

Identifiers

NCT: NCT07075770 · PNRR-MCNT2-2023-12377518

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗