Alzheimer Disease, Alzheimer Disease, Early Onset
Conditions
Brief summary
New amyloid-targeting drugs for Alzheimer's disease (AD) offer minimal or unclear efficacy and often cause adverse events, highlighting the need for new therapies. In recent years, repetitive transcranial magnetic stimulation (rTMS) has shown increasing success. A recent randomized, double-blind, sham-controlled, phase 2 demonstrated promising results from a 24-week rTMS treatment protocol targeting the precuneus. This brain region is considered a main hub of the human brain connectome and a prominent area of AD pathology. The results showed stable cognitive performance and increased brain activity in the treatment group, whereas the sham group worsened. A replication study is planned to further investigate the working mechanism of precuneus-rTMS in AD and to improve understanding of its therapeutic potential.
Interventions
DEVICEsham repetitive transcranial magnetic stimulation
20 Hz sham repetitive transcranial magnetic stimulation targeted at the precuneus
DEVICErepetitive transcranial magnetic stimulation
20 Hz repetitive transcranial magnetic stimulation targeted at the precuneus
Sponsors
Willem de Haan
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
50 Years to 85 Years
Healthy volunteers
No
Inclusion criteria
* Biomarker-supported Alzheimer's disease (abnormal CSF p-tau/Aβ42 ratio of \> 0.023 or amyloid PET positive). * Between 50 and 85 years old. * Clinical Dementia Rating (CDR) score of 0.5 or 1. * Mini-Mental State Examination (MMSE) score between 18 and 27. * Presence of a caregiver.
Exclusion criteria
* Medical history of neurodegenerative diseases other than AD, stroke, or epilepsy. * Severe psychiatric dysregulation, hampering successful study participation and leading to possible cognitive impairment. Eligibility for participation will be based on clinical evaluation by an expert neurologist and/or psychiatrist. * Extensive cerebrovascular damage on MRI classified as Fazekas level 2 or 3. Patients with abnormalities classified as Fazekas level 3 are excluded. For Fazekas level 2, patient's eligibility for participation will be evaluated by an expert neurologist. * Presence of metal in the head or cranial/thoracic implants, including cochlear implants. * Cholinesterase inhibitors with unstable dosage in the last 2 months. * Extreme claustrophobia or metallic objects in or on the body, preventing MRI and MEG examination. * Previous rTMS treatment (for blinding reasons).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| CDR - Sum of Boxes | from enrollment to 3 month follow-up | Clinical dementia rating - sum of boxes |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Neuropsychological evaluation: Visual Association Test (VAT) | baseline to week 24 (post-treatment) | Detects signs of anterograde amnesia through object-pair associations. Unit: Number of correct associations (maximum score: 12) |
| Neuropsychological evaluation: Stroop Color and Word Test | baseline to week 24 (post-treament) | Evaluates cognitive flexibility, inhibition, and processing speed. Unit: Seconds (per condition), Errors (count) |
| Neuropsychological evaluation: WAIS-III Digit Span (Forward and Backward) | baseline to week 24 (post-treatment) | Assesses attention and verbal working memory. Unit: Span length (maximum correctly repeated digit sequences) |
| Neuropsychological evaluation: Rey Auditory Verbal Learning Test (RAVLT) | baseling to week 24 (post-treatment) | Evaluates verbal learning and declarative memory. Immediate recall (Trials I-V) Unit: Total number of words recalled Delayed recall Unit: Number of words recalled Recognition Unit: Number of correct recognitions |
| Magnetoencephalography (MEG): Joint Permutation Entropy (JPE) | baseline to week 24 (post-treatment) | A nonlinear measure of signal complexity and diversity in joint time series. |
| Magnetoencephalography (MEG): Spectral analysis | from baseline to week 24 (post-treatment) | Power spectral density (µV²/Hz) computed for different frequency bands . |
| Cerebrospinal fluid (CSF) biomarkers | from baseline to week 24 (post-treatment) | Cerebrospinal fluid (CSF) biomarkers are typically reported in picograms per milliliter (pg/mL). This applies to: Amyloid-beta (Aβ₁-₄₂): pg/mL Total tau (t-tau): pg/mL Phosphorylated tau (p-tau, e.g., p-tau181): pg/mL |
| Neuropsychological evaluation: Trail Making Test | from baseline to week 24 (post-treatment) | Assesses visual attention, processing speed, and task switching. Unit: Seconds (completion time) |
| Amsterdam instrumental activities of daily living questionnaire (AmsterdamiADL); | baseline to 3 month follow-up | The Amsterdam Instrumental Activities of Daily Living (A-IADL) Questionnaire is a validated tool that assesses cognitive functioning through everyday tasks, with scores ranging from approximately 20 (severe impairment) to 70 (no impairment). |
| Mini mental state examination (MMSE) | baseline to 3-month follow up. | The mini-mental state examination (MMSE) test is a 30-point questionnaire that is used extensively in clinical and research settings to measure cognitive impairment. Higher is better. |
| Neuropsychiatric Inventory Questionnaire (NPI-Q) | baseline to 3 month follow up | The Neuropsychiatric Inventory Questionnaire (NPI-Q) is a brief, informant-based tool that assesses 12 neuropsychiatric symptoms in dementia, with total severity scores ranging from 0 to 36 and distress scores from 0 to 60. |
| Quick Inventory of Depressive Symptomatology (QIDS) | baseline to 3-month follow up | The Quick Inventory of Depressive Symptomatology (QIDS) is a clinician-rated tool that measures the severity of depressive symptoms, with total scores ranging from 0 (no depression) to 27 (severe depression). |
| Magnetoencephalography (MEG): Corrected Amplitude Envelope Correlation (AEC-c) | From baseline to week 24 (post-treatment) | Correlation of the amplitude envelopes of band-pass filtered signals, corrected for signal leakage. |
| Neuropsychological evaluation: Verbal Fluency Test | baseline to week 24 (post-treatment) | Measures verbal production and executive functioning. Phonemic fluency (letters D, A, T) Unit: Number of words per 1 minute Semantic fluency (animals) Unit: Number of words per 1 minute |
| Magnetoencephalography (MEG): Phase Lag Index (PLI) | baseline to week 24 (post-treatment) | A measure of phase synchronization that is robust to volume conduction. |
Countries
Netherlands
Contacts
CONTACTWillem De Haan, PhD
Outcome results
None listed