Promising outcomes 5 weeks after a surgical cervical shunting procedure to unclog cerebral lymphatic systems in a patient with Alzheimer’s disease

Recently, the glymphatic system has been recognised as an important ‘waste solutes transport channel’ within the brain.1 Studies have shown that blockage of the glymphatic system leads to increased beta-amyloid deposits, accelerating the onset and progression of Alzheimer’s disease (AD).1 2 Given that cervical lymph nodes receive cerebrospinal fluid from the brain’s glymphatic system,3 4 we speculated that decompression of the lymphatic trunk and cervical lymphatic–venous anastomosis (LVA) could facilitate the flow of cerebrospinal fluid in the cranial glymphatic system, potentially accelerating the clearance of harmful beta-amyloid and tau proteins. We collaborated with surgeons who specialise in LVA supermicrosurgery for maxillofacial tumours and lymphoedema to develop a procedure to relieve the blockage of the glymphatic system. This surgery employs supermicrosurgery techniques to create LVA connecting the bilateral cervical, deep lymphatic vessels to the veins, resulting in lymphatic trunk decompression, which allows the lymph fluid in the high-pressure lymphatic vessels to flow into the low-pressure venous system. The goal of the minimally invasive surgery is to enhance the removal of proteins, such as beta-amyloid and tau, from the brain’s lymphatic systems to the maxillofacial lymphatic vessels, unclogging protein blockages within the brain. This extracranial procedure is safer than intracranial approaches. Following a thorough assessment of the safety and potential efficacy of the procedure, and securing ethics approval from the Ethics Committees of the Shanghai Mental Health Center and Shanghai Ninth People’s Hospital, we initiated an investigator-initiated trial of the ‘Cervical Shunting to Unclog cerebral Lymphatic Systems (CSULS) surgical procedure’ (registration number: ChiCTR2400084617).

Xie et al previously reported performing LVA surgery on patients with dementia and shared pre-surgery and post-surgery videos of patients.5 The CSULS surgical approach and location differ from those used by Xie et al. Another important distinction is in the diagnoses: our patient met the biological diagnostic criteria for AD, as outlined by the National Institute on Aging-Alzheimer’s Association criteria,6 whereas Xie et al’s patients did not. Moreover, we compared biological measures, such as positron emission tomography (PET) scans and magnetic resonance imaging (MRI), before and after CSULS to confirm its efficacy.

As of 25 March 2024, six individuals have undergone the CSULS procedure. Their main postoperative side effect was delirium within 24 hours after surgery, possibly due to anaesthesia. The delirium improved within 72 hours. No other adverse reactions were observed. Cognitive assessments showed slight improvements in all six patients, especially in attention and reaction speed. Most caregivers reported improvements in patients’ language and mood. A comprehensive report on all six cases will be released after follow-up completion. Here, we present the first case with completed follow-up, including PET, MRI scans and psychological assessments. The positive results of this initial case suggest that this innovative procedure could become an important new approach to the prevention and management of AD.

A 70-year-old woman was brought to the Alzheimer’s Disease and Related Disorders Center of Shanghai Jiao Tong University by her daughter on 30 December 2023, who reported gradual memory loss with intermittent anxiety and depression since 2018. Her memory decline accelerated over the past year, following femur and lumbar vertebrae fractures. The patient frequently could not recall events that occurred just a few hours prior. On 25 December 2023, she was evaluated at the Memory Clinic in Hangzhou, where PET scans with AV45 and tau AV1451 tracer imaging identified beta-amyloid depositions and positive tau signals, which were more pronounced in the right cerebral cortex. Additionally, her brain MRI revealed medial temporal atrophy, level 3 on the right and level 2 on the left. Based on these results, she met the diagnostic criteria for AD as outlined by the National Institute on Aging-Alzheimer’s Association and the International Working Group.6 7 Hearing about our trial, her daughter brought her to the Alzheimer’s Disease and Related Disorders Center for treatment, stating: “We hope that a surgical intervention can be conducted to prevent further deterioration of her memory.”

After obtaining informed consent from the patient and her daughter, we conducted psychological tests, routine blood examinations and fluorodeoxyglucose PET/MRI, which confirmed her eligibility for the intervention. She underwent the CSULS surgical procedure on 13 January 2024. Three days after the surgery, the patient’s post-anaesthetic reactions, including unsteady walking and a dazed expression, had resolved. On the seventh day post-surgery, her daughter reported improved memory, stating: “She can remember the neighbour she met yesterday now!”

Five weeks after the surgery, clinical assessments found improved cognitive function: the Mini-Mental Status Examination score increased from 5 to 7, and the score on the Clinical Dementia Rating-sum of boxes test improved from 10 to 8. Her depressive mood had resolved: the Geriatric Depression Scale score dropped from 9 to 0. Her PET scan provided objective evidence of this improvement (figure 1). The ¹⁸F-fluorodeoxyglucose PET showed an overall improvement in brain glucose metabolism, which was most evident in the right frontal lobe. The T-sum within AD regions dropped from 92 176.3 to 81 949.8 (normal 95% prediction limit: 11 089.7). The maximum standardised uptake value increased from 8.52 to 8.98. The tau-PET showed an overall reduction of tau in the brain. Furthermore, the index of the diffusion tensor image analysis along the perivascular space increased from 1.19 to 2.26, indicating improved brain health.

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Four months after the surgery, during a phone interview, the patient’s daughter stated: “My mother’s memory is stabilising and improving, and she is able to complete household chores every day.”

Footnotes

• X: @Xia li

• Contributors: XL, ZW and ZR shared joint correspondence in this work. XL performed statistical analysis and drafted the main manuscript text. XL, ZR, CZ, YF, MX and JS helped the patient and acquired the data. ZW, ZZ, XL and ZR were involved in the study conception and participated in design and coordination. All the authors are acknowledged.

• Funding: This work was supported by the National Key R&D Program of China (2023YFC36003200), Shanghai Mental Health Center investigator-initiated trial programme (2024-TX-001), Shanghai's Top Priority Research Center (2022ZZ01017), and CAMS Innovation Fund for Medical Sciences (2019-12M-5-037).

• Competing interests: None declared.

• Provenance and peer review: Not commissioned; externally peer reviewed.

Ethics statements

Patient consent for publication:

Consent obtained from parent(s)/guardian(s).

Ethics approval:

This study involves human participants and was approved by the Shanghai Mental Health Center Ethics Committee (SMHC-2024-01) and Shanghai Ninth People’s Hospital Ethics Committee (SH9H-2023-T423-2). Participants gave informed consent to participate in the study before taking part.

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