Low-Dose Radiotherapy for Alzheimer's Disease

Official title

Low-Dose Radiotherapy for Alzheimer's Disease: A Phase I/II Open-Label Feasibility and Safety Study (LDRT-MIND Trial)

Overview

To evaluate the safety and tolerability of low-dose whole brain radiotherapy (WBRT) delivered as an induction course of 0.3 Gy × 10 fractions (3.0 Gy total) followed by 12 months of monthly maintenance LDRT (0.3 Gy × 10 fractions; 3.0 Gy total) in patients with Alzheimer's disease or dementia with inflammatory components

Interventions

• Radiation Low Dose Radiation Therapy
  Low dose whole brain radiotherapy delivered as an induction course of 10 fractions followed by 12 months of monthly maintenance LDRT in 10 fractions starting 2 months post-induction

Primary outcome measures

• Safety, As Measured By Incidence of Grade 3 or Higher Treatment-Related Adverse Events [Time frame: From the first induction radiotherapy fraction through 30 days after the final monthly maintenance fraction (acute monitoring period), approximately 13 to 15 months]

Secondary outcome measures (1)

• Cognitive Preservation, As Measured By Change in Montreal Cognitive Assessment (MoCA) Score From Baseline to Month 12 [Time frame: Baseline to Month 12, with MoCA assessed longitudinally across the maintenance period and at a standalone Month 12 cognitive endpoint visit]

Eligibility criteria

Inclusion criteria

• Age ≥50 years at time of enrollment
• Externally confirmed diagnosis by a neurologist or geriatric psychiatrist (at Renaissance Institute, collaborating neurologist Dr. Sherif Makar, MD of Charis Neurology is available for diagnostic consultation) of one of the following: a. Alzheimer's disease (per NIA-AA 2011 or 2018 criteria) b. Frontotemporal dementia with documented inflammatory features c. Dementia with Lewy bodies with elevated inflammatory CSF markers d. Other neurodegenerative dementia with confirmed inflammatory component (elevated CSF IL-6, IL-1β, or TNF-α; or neuroimaging evidence of neuroinflammation)
• MoCA score 10-25 at baseline screening (moderate-to-mild cognitive impairment range)
• Karnofsky Performance Status (KPS) ≥60 or ECOG Performance Status ≤2
• Medically stable and capable of receiving radiation therapy as assessed by the treating radiation oncologist
• Reliable caregiver or informant able to accompany the patient to ≥80% of scheduled visits
• Written informed consent from patient (if decision-making capacity is preserved) and/or legally authorized representative (LAR); caregiver co-consent required
• Life expectancy ≥18 months in the opinion of the treating physician
• Ability and willingness to comply with monthly clinic visits for the 12-month maintenance period

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Exclusion criteria

• Prior whole brain or partial brain radiotherapy of any dose at any time
• Active systemic malignancy requiring concurrent oncologic treatment
• Implanted device contraindicated with radiation therapy (pacemaker, cochlear implant, deep brain stimulator, or equivalent)
• Brain MRI demonstrating any of the following: (a) more than 4 cerebral microhemorrhages on susceptibility-weighted imaging (SWI) or gradient echo (GRE) sequences; (b) more than 1 area of superficial cortical siderosis; (c) severe white matter disease (Fazekas grade 3); or (d) any macrohemorrhage or hemosiderin-stained lesion >10 mm. These thresholds are adapted from established AD trial imaging exclusion criteria to minimize enrollment of patients with advanced cerebrovascular disease or pre-existing hemorrhagic risk factors.
• Known active cerebral amyloid angiopathy-related inflammation (CAA-ri) or amyloid-related beta-angiitis (ABRA), whether confirmed by biopsy, CSF analysis, or neuroimaging features consistent with active leptomeningeal or parenchymal amyloid-related inflammation
• Active autoimmune encephalitis in acute phase (patients in stable chronic phase are eligible)
• Uncontrolled systemic infection or active sepsis at enrollment
• Severe psychiatric comorbidity (active psychosis, active suicidal ideation) impairing protocol compliance or safety assessment
• Concurrent enrollment in another interventional trial targeting cognitive decline or neuroinflammation
• Pregnancy or lactation; women of childbearing potential must use adequate contraception
• Inability to lie flat and still for radiation delivery (approximately 10-15 minutes per session)
• MoCA <10 at baseline screening (severe dementia; insufficient cognitive range for endpoint assessment)

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

Healthy volunteers: No

Study design

Allocation

N/A

Model

Single group

Masking

Open label

Primary purpose

Treatment

Study locations

United States · 1 center

• Renaissance Institute of Precision Oncology & Radiosurgery — Winter Park

Publications

• McKhann GM, Knopman DS, Chertkow H, Hyman BT, Jack CR Jr, Kawas CH, Klunk WE, Koroshetz WJ, Manly JJ, Mayeux R, Mohs RC, Morris JC, Rossor MN, Scheltens P, Carrillo MC, Thies B, Weintraub S, Phelps CH. The diagnosis of dementia due to Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. Alzhei PMID 21514250
• Jack CR Jr, Bennett DA, Blennow K, Carrillo MC, Dunn B, Haeberlein SB, Holtzman DM, Jagust W, Jessen F, Karlawish J, Liu E, Molinuevo JL, Montine T, Phelps C, Rankin KP, Rowe CC, Scheltens P, Siemers E, Snyder HM, Sperling R; Contributors. NIA-AA Research Framework: Toward a biological definition of Alzheimer's disease. Alzheimers Dement. 2018 Apr;14(4):535-562. doi: 10.1016/j.jalz.2018.02.018. PMID 29653606
• Nasreddine ZS, Phillips NA, Bedirian V, Charbonneau S, Whitehead V, Collin I, Cummings JL, Chertkow H. The Montreal Cognitive Assessment, MoCA: a brief screening tool for mild cognitive impairment. J Am Geriatr Soc. 2005 Apr;53(4):695-9. doi: 10.1111/j.1532-5415.2005.53221.x. PMID 15817019
• Julayanont P, Brousseau M, Chertkow H, Phillips N, Nasreddine ZS. Montreal Cognitive Assessment Memory Index Score (MoCA-MIS) as a predictor of conversion from mild cognitive impairment to Alzheimer's disease. J Am Geriatr Soc. 2014 Apr;62(4):679-84. doi: 10.1111/jgs.12742. Epub 2014 Mar 17. PMID 24635004
• Tang Q, Cheng Y. Enteral Nutrition: Based on the Combination of Nutrison Fibre and TPF-DM with A Marine Biological-Based Active Polysaccharide Preparation. Comput Math Methods Med. 2022 Jun 30;2022:6213716. doi: 10.1155/2022/6213716. eCollection 2022. PMID 35813412
• Picard M. Blood mitochondrial DNA copy number: What are we counting? Mitochondrion. 2021 Sep;60:1-11. doi: 10.1016/j.mito.2021.06.010. Epub 2021 Jun 19. PMID 34157430
• Wilson GD, Wilson TG, Hanna A, Fontanesi G, Kulchycki J, Buelow K, Pruetz BL, Michael DB, Chinnaiyan P, Maddens ME, Martinez AA, Fontanesi J. Low Dose Brain Irradiation Reduces Amyloid-beta and Tau in 3xTg-AD Mice. J Alzheimers Dis. 2020;75(1):15-21. doi: 10.3233/JAD-200030. PMID 32280098
• Marples B, McGee M, Callan S, Bowen SE, Thibodeau BJ, Michael DB, Wilson GD, Maddens ME, Fontanesi J, Martinez AA. Cranial irradiation significantly reduces beta amyloid plaques in the brain and improves cognition in a murine model of Alzheimer's Disease (AD). Radiother Oncol. 2016 Jan;118(1):43-51. doi: 10.1016/j.radonc.2015.10.019. Epub 2015 Nov 23. PMID 26615717

Identifiers

NCT: NCT07693140 · LDRT-MIND

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗