Evaluation of Glymphatic System Activity Using Diffusion Tensor Imaging Analysis Along the Perivascular Space (DTI-ALPS) in Alzheimer’s Disease

Öz

Aim: The glymphatic system is a recently discovered waste drainage system that facilitates the movement of cerebrospinal fluid through the brain's perivascular spaces and aids in removing soluble proteins. The Diffusion Tensor Imaging (DTI-ALPS) index analysis is a modern method used to evaluate the movement of water molecules in these spaces by measuring the diffusion coefficient. This study aimed to examine glymphatic system function in Alzheimer's disease (AD) patients compared to healthy controls (HC) using the DTI-ALPS method and to analyze its relationship with cognitive disorders. Methods:DTI data from 59 AD patients and 59 HC were obtained by downloading medical data from the Alzheimer's Disease Neuroimaging Initiative (ADNI) platform. Using DSI Studio software, the diffusivities of the DTI data were extracted, and DTI-ALPS indices were calculated. Correlation analysis evaluated the relationship between the DTI-ALPS index and clinical features. Results:The findings indicated that the DTI-ALPS index was significantly lower in AD patients compared to HC (p = 0.042). Furthermore, the DTI-ALPS index showed a significant correlation with the Functional Activities Questionnaire (FAQ) (r = -0.214, p = 0.020) and the Mini-Mental State Examination (MMSE) (r = 0.225, p = 0.014) Conclusions:The study demonstrated that AD individuals have impaired glymphatic system function, as indicated by the DTI-ALPS index, which correlates with worse cognitive performance. These findings support early diagnosis methods for AD. A better understanding of glymphatic system function may provide new perspectives for monitoring AD progression.

Anahtar Kelimeler

• Alzheimer
• Brain Perivascular Space
• Diffusion Tensor Imaging
• G-lymphatic System
• G-lymphatic Clearance System

Etik Beyan

The ethics committee approval has been obtained from Uskudar University Non Interventional Research Ethics Committee report number of 61351342/MAY 2023-12 (29 May 2023).

Teşekkür

Data collection and sharing for this project was funded by the Alzheimer's Disease Neuroimaging Initiative (ADNI) (National Institutes of Health Grant U01 AG024904) and DOD ADNI (Department of Defense award number W81XWH-12-2-0012). ADNI is funded by the National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering, and through generous contributions from the following: AbbVie, Alzheimer’s Association; Alzheimer’s Drug Discovery Foundation; Araclon Biotech; BioClinica, Inc.; Biogen; Bristol-Myers Squibb Company; CereSpir, Inc.; Cogstate; Eisai Inc.; Elan Pharmaceuticals, Inc.; Eli Lilly and Company; EuroImmun; F. Hoffmann-La Roche Ltd and its affiliated company Genentech, Inc.; Fujirebio; GE Healthcare; IXICO Ltd.; Janssen Alzheimer Immunotherapy Research & Development, LLC.; Johnson & Johnson Pharmaceutical Research & Development LLC.; Lumosity; Lundbeck; Merck & Co., Inc.; Meso Scale Diagnostics, LLC.; NeuroRx Research; Neurotrack Technologies; Novartis Pharmaceuticals Corporation; Pfizer Inc.; Piramal Imaging; Servier; Takeda Pharmaceutical Company; and Transition Therapeutics. The Canadian Institutes of Health Research is providing funds to support ADNI clinical sites in Canada. Private sector contributions are facilitated by the Foundation for the National Institutes of Health (www.fnih.org). The grantee organization is the Northern California Institute for Research and Education, and the study is coordinated by the Alzheimer’s Therapeutic Research Institute at the University of Southern California. ADNI data are disseminated by the Laboratory for Neuro Imaging at the University of Southern California. I would like to express my gratitude to Üsküdar University for their invaluable support during the preparation of my doctoral thesis, from which this study originates.

Alzheimer Hastalığında Perivasküler Alan Boyunca Difüzyon Tensor Görüntüleme Analizi (DTI-ALPS) Kullanılarak G-lenfatik Sistem Aktivitesinin Değerlendirilmesi

Öz

Amaç: G-lenfatik sistem, beyin perivasküler boşlukları boyunca beyin omurilik sıvısının hareketini kolaylaştıran ve çözünür proteinlerin uzaklaştırılmasına yardımcı olan, yakın zamanda keşfedilmiş bir atık drenaj sistemidir. Difüzyon Tensör Görüntüleme (DTI-ALPS) indeks analizi, bu boşluklardaki su moleküllerinin hareketini difüzyon katsayısını ölçerek değerlendirmede kullanılan modern bir yöntemdir. Bu çalışma, DTI-ALPS yöntemi kullanılarak Alzheimer hastalığı (AH) olan bireylerde g-lenfatik sistem fonksiyonunu sağlıklı kontrollerle (SK) karşılaştırmayı ve bilişsel bozukluklarla olan ilişkisini incelemeyi amaçlamıştır. Yöntem: 59 AH hastasına ve 59 sağlıklı kontrole ait DTI verileri, Alzheimer Hastalığı Nörogörüntüleme Girişimi (ADNI) platformundan indirilen tıbbi veriler kullanılarak elde edilmiştir. DSI Studio yazılımı kullanılarak DTI verilerinin difüziviteleri çıkarılmış ve DTI-ALPS indeksleri hesaplanmıştır. Korelasyon analizi, DTI-ALPS indeksi ile klinik özellikler arasındaki ilişkiyi değerlendirmek için uygulanmıştır. Bulgular: Bulgular, AH hastalarında DTI-ALPS indeksinin sağlıklı kontrollere kıyasla anlamlı derecede düşük olduğunu göstermiştir (p = 0.042). Ayrıca DTI-ALPS indeksi, Fonksiyonel Aktivite Anketi (FAQ) (r = -0.214, p = 0.020) ve Mini Mental Durum Değerlendirmesi (MMSE) (r = 0.225, p = 0.014) ile anlamlı korelasyon göstermiştir. Sonuç: Bu çalışma, DTI-ALPS indeksiyle gösterildiği üzere Alzheimer hastalarında g-lenfatik sistem fonksiyonunun bozulduğunu ve bunun daha kötü bilişsel performansla ilişkili olduğunu ortaya koymuştur. Bu bulgular, Alzheimer hastalığının erken tanısına yönelik yöntemleri desteklemekte olup, g-lenfatik sistem fonksiyonunun daha iyi anlaşılması hastalığın ilerlemesinin izlenmesinde yeni bakış açıları sağlayabilir.

Anahtar Kelimeler

• Alzheimer Hastalığı
• Beyin Perivasküler Alanı
• Difüzyon Tensör Görüntüleme
• G-lenfatik Sistem

Etik Beyan

Etik kurul onayı, Üsküdar Üniversitesi Girişimsel Olmayan Araştırmalar Etik Kurulu’ndan 61351342/MAY 2023-12 (29 Mayıs 2023) rapor numarası ile alınmıştır.

Teşekkür

Bu araştırmanın veri toplama ve paylaşımı, Alzheimer’s Disease Neuroimaging Initiative (ADNI) (Ulusal Sağlık Enstitüleri Hibe U01 AG024904) ve DOD ADNI (Savunma Bakanlığı ödül numarası W81XWH-12-2-0012) tarafından finanse edilmiştir. ADNI, Ulusal Yaşlanma Enstitüsü, Ulusal Biyomedikal Görüntüleme ve Biyomühendislik Enstitüsü tarafından ve aşağıdaki kuruluşların cömert katkılarıyla desteklenmektedir: AbbVie, Alzheimer Derneği; Alzheimer İlaç Keşif Vakfı; Araclon Biotech; BioClinica, Inc.; Biogen; Bristol-Myers Squibb Company; CereSpir, Inc.; Cogstate; Eisai Inc.; Elan Pharmaceuticals, Inc.; Eli Lilly and Company; EuroImmun; F. Hoffmann-La Roche Ltd ve bağlı şirketi Genentech, Inc.; Fujirebio; GE Healthcare; IXICO Ltd.; Janssen Alzheimer Immunotherapy Research & Development, LLC.; Johnson & Johnson Pharmaceutical Research & Development LLC.; Lumosity; Lundbeck; Merck & Co., Inc.; Meso Scale Diagnostics, LLC.; NeuroRx Research; Neurotrack Technologies; Novartis Pharmaceuticals Corporation; Pfizer Inc.; Piramal Imaging; Servier; Takeda Pharmaceutical Company; ve Transition Therapeutics. Kanada’daki ADNI klinik merkezlerini desteklemek için Canadian Institutes of Health Research fon sağlamaktadır. Özel sektör katkıları, Ulusal Sağlık Enstitüleri Vakfı (www.fnih.org ) aracılığıyla kolaylaştırılmaktadır. Hibe alan kuruluş Northern California Institute for Research and Education olup, çalışma University of Southern California’daki Alzheimer’s Therapeutic Research Institute tarafından koordine edilmektedir. ADNI verileri, University of Southern California’daki Laboratory for Neuro Imaging tarafından dağıtılmaktadır. Bu çalışmanın kaynağı olan doktora tezimin hazırlanması sürecinde verdikleri değerli destek için Üsküdar Üniversitesi’ne şükranlarımı sunarım.

Kaynakça

1. 1. Iliff JJ, Wang M, Liao Y, et al. A paravascular pathway facilitates CSF flow through the brain parenchyma and the clearance of interstitial solutes, including amyloid β. Science Translational Medicine 2012; 4(147): 147ra111.
2. 2. Jessen NA, Munk ASF, Lundgaard I, et al. The glymphatic system: a beginner’s guide. Neurochemical Research 2015; 40: 2583-2599.
3. 3. Heo CM, Lee WH, Park BS, et al. Glymphatic dysfunction in patients with end-stage renal disease. Frontiers in Neurology 2022; 12: 2588.
4. 4. Plog BA, Nedergaard M. The glymphatic system in central nervous system health and disease: past, present, and future. Annual Review of Pathology: Mechanisms of Disease 2018; 13: 379-394.
5. 5. Shetty AK, Zanirati G. The interstitial system of the brain in health and disease. Aging and disease 2020; 11(1): 200.
6. 6. Silva I, Silva J, Ferreira R, et al. Glymphatic system, AQP4, and their implications in Alzheimer’s disease. Neurological research and practice 2021; 3: 1-9.
7. 7. Taoka T, Ito R, Nakamichi R, et al. Reproducibility of diffusion tensor image analysis along the perivascular space (DTI-ALPS) for evaluating interstitial fluid diffusivity and glymphatic function: CHanges in Alps index on Multiple conditiON acquIsition eXperiment (CHAMONIX) study. Japanese Journal of Radiology 2022; 40(2): 147-158.
8. 8. Iliff JJ, Wang M, Zeppenfeld DM et al. Cerebral arterial pulsation drives paravascular CSF-interstitial fluid exchange in the murine brain. J Neurosci 2013; 33: 18190-18199.

9. 9. Fleischman D, Berdahl JP, Zaydlarova J et al. Cerebrospinal fluid pressure decreases with older age. PLoS ONE 2012; 7:e52664.
10. 10. Chen RL, Kassem NA, Redzic ZB et al. Age-related changes in choroid plexus and blood-cerebrospinal fluid barrier function in the sheep. Exp Gerontol 2009; 44: 289-296.
11. 11. Wichmann TO, Damkier HH, Pedersen M. A brief overview of the cerebrospinal fluid system and its implications for brain and spinal cord diseases. Frontiers in Human Neuroscience 2022; 15: 737217.
12. 12. Iliff JJ, Chen MJ, Plog BA, et al. Impairment of glymphatic pathway function promotes tau pathology after traumatic brain injury. Journal of Neuroscience 2014; 34(49): 16180-16193.
13. 13. Peng W, Achariyar TM, Li B, et al. Suppression of glymphatic fluid transport in a mouse model of Alzheimer’s disease. Neurobiology of disease 2016; 93: 215-225.
14. 14. Kress BT, Iliff JJ, Xia M, et al. Impairment of paravascular clearance pathways in the aging brain. Annals of neurology 2014; 76(6): 845-861.
15. 15. Rasmussen MK, Mestre H, Nedergaard M. The glymphatic pathway in neurological disorders. The Lancet Neurology 2018; 17(11), 1016-1024.
16. 16. Oliver G, Kipnis J, Randolph GJ, Harvey NL. The lymphatic vasculature in the 21st century: novel functional roles in homeostasis and disease. Cell 2020; 182(2): 270-296.
17. 17. Zeppenfeld DM, Simon M, Haswell JD, D’Abreo D, Murchison C, et al. Association of perivascular localization of aquaporin-4 with cognition and Alzheimer disease in aging brains. JAMA neurology 2017; 74(1): 91-99.
18. 18. Reeves BC, Karimy JK, Kundishora AJ, Mestre H, et al. Glymphatic system impairment in Alzheimer’s disease and idiopathic normal pressure hydrocephalus. Trends in molecular medicine 2020; 26(3): 285-295.
19. 19. Zhang C, Chen J, Lu H. Expression of aquaporin-4 and pathological characteristics of brain injury in a rat model of traumatic brain injury. Molecular Medicine Reports 2015; 12(5): 7351-7357.
20. 20. Crestini A, Santilli F, Martellucci S, et al. Prions and neurodegenerative diseases: a focus on Alzheimer’s disease. Journal of Alzheimer’s Disease 2022; 85(2): 503-518.
21. 21. Moses J, Sinclair B, Law M, et al. Automated methods for detecting and quantitation of enlarged perivascular spaces on MRI. Journal of Magnetic Resonance Imaging 2023; 57(1): 11-24.
22. 22. Taoka T, Masutani Y, Kawai H, et al. Evaluation of glymphatic system activity with the diffusion MR technique: diffusion tensor image analysis along the perivascular space (DTI-ALPS) in Alzheimer’s disease cases. Japanese journal of radiology 2017; 35: 172-178.
23. 23. Achariyar TM, Li B, Peng W, et al. Glymphatic distribution of CSF-derived apoE into brain is isoform specific and suppressed during sleep deprivation. Molecular neurodegeneration 2016; 11: 1-20.
24. 24. Hauglund NL, Pavan C, Nedergaard M. Cleaning the sleeping brain–the potential restorative function of the glymphatic system. Current Opinion in Physiology 2020; 15: 1-6.
25. 25. Bae YJ, Choi BS, Kim JM, et al. Altered glymphatic system in idiopathic normal pressure hydrocephalus. Parkinsonism & Related Disorders 2021; 82: 56-60.
26. 26. Lee HJ, Lee DA, Shin KJ, et al. Glymphatic system dysfunction in obstructive sleep apnea evidenced by DTI-ALPS. Sleep Medicine 2022; 89: 176-181.
27. 27. Lynch M, Pham W, Sinclair B, et al. Perivascular spaces as a potential biomarker of Alzheimer’s disease. Frontiers in neuroscience 2022; 16: 1021131.
28. 28. Taglino F, Cumbo F, Antognoli G, et al. An ontology-based approach for modelling and querying Alzheimer’s disease data. BMC Medical Informatics and Decision Making 2023; 23(1): 153.
29. 29. Folstein MF, Folstein SE, McHugh PR. Mini Mental State: A practical method for grading the cognitive state of patients for the clinician. Journal of Psychiatric Research 1975; 12: 189-198.
30. 30. Pfeffer RI, Kurosaki TT, Harrah Jr CH, et al. Measurement of functional activities in older adults in the community. Journal of gerontology 1982; 37(3): 323-329.
31. 31. Yang DX, Sun Z, Yu MM, et al. Associations of MRI‐derived glymphatic system impairment with global white matter damage and cognitive impairment in mild traumatic brain injury: a DTI‐ALPSstudy. Journal of Magnetic Resonance Imaging 2024; 59(2): 639-647.
32. 32. Okazawa H, Nogami M, Ishida S, et al. PET/MRI multimodality imaging to evaluate changes in glymphatic system function and biomarkers of Alzheimer’s disease. Scientific Reports 2024; 14(1): 12310.
33. 33. Chang HI, Huang CW, Hsu SW, et al. Gray matter reserve determines glymphatic system function in young‐onset Alzheimer’s disease: evidenced by DTI‐ALPS and compared with age‐matched controls. Psychiatry and Clinical Neurosciences 2023; 77(7): 401-409.
34. 34. Liang T, Chang F, Huang Z, et al. Evaluation of glymphatic system activity by diffusion tensor image analysis along the perivascular space (DTI-ALPS) in dementia patients. The British journal of radiology 2023; 96(1146): 20220315.
35. 35. Kamagata K, Andica C, Takabayashi K, et al. Association of MRI indices of glymphatic system with amyloid deposition and cognition in mild cognitive impairment and Alzheimer disease. Neurology 2022; 99(24): e2648-e2660.
36. 36. Zhang X, Wang Y, Jiao B, et al. Glymphatic system impairment in Alzheimer’s disease: associations with perivascular space volume and cognitive function. European Radiology 2024; 34(2): 1314-1323.
37. 37. Opara JA. Activities of daily living and quality of life in Alzheimer disease. Journal of medicine and life 2012; 5(2): 162.
38. 38. Marshall GA, Amariglio RE, Sperling RA, et al. Activities of daily living: where do they fit in the diagnosis of Alzheimer’s disease?. Neurodegenerative disease management 2012; 2(5): 483-491.
39. 39. Jin Y, Zhang W, Yu M, et al. Glymphatic system dysfunction in middle-aged and elderly chronic insomnia patients with cognitive impairment evidenced by diffusion tensor imaging along the perivascular space (DTI-ALPS). Sleep Medicine 2024; 115: 145-151.