Dr. Cavallari will present studies relevant to the recently discovered glymphatic pathway of clearance, with particular emphasis on ongoing studies at the Center for Neurological Imaging. The glymphatic pathway is considered to play a substantial role in the clearance of brain waste, including neurotoxins implicated in the pathobiology of neurodegenerative disease, such as Alzheimer’s disease. Studies in animal models showed that this mechanism of clearance is particularly active during sleep. The characterization of the glymphatic system in humans would have profound implications for our understanding of the core functions of sleep, as well as the pathogenesis of neurodegenerative diseases. Preliminary findings, including ours, support the presence of a similar mechanism of clearance in humans.

1. The Glymphatic System in Sleep
and Neurodegenerative Diseases
Michele Cavallari
MD, PhD
Assistant Professor of Radiology
Harvard Medical School
Brigham and Women’s Hospital
Center for Neurological Imaging

2. No lymphatic vessels
High metabolic rate
Neurotoxic waste

3. Glymphatic System
Maiken Nedergaard

4. Jonathan Kipnis

5. Glymphatic Clearance of Beta-Amyloid
During Sleep

6. Why We Sleep
Van M. Savage & Geoffrey B. West
Energy Restoration
ATP <–> Adenosine
Charles A. Czeisler

8. Why We Sleep
Energy Restoration
ATP <–> Adenosine
Memory Consolidation
Insight, Creativity, Problem Solving
Maintenance of Brain
Connectivity
Waste Clearance

9. Is There a Glymphatic System
in Humans?

11. Enlarged Perivascular Spaces (EPVS)

13. Study Protocol
10pm 11pm 12am 1am 2am 3am 4am 5am 6am 7am 8am 9am 10am 11am 12pm 1pm 2pm 3pm 4pm 5pm 6pm 7pm 8pm 9p
Day
-6 HOME SLEEP EPISODE
-5 HOME SLEEP EPISODE
-4 HOME SLEEP EPISODE
-3 HOME SLEEP EPISODE
-2 HOME SLEEP EPISODE
-1 HOME SLEEP EPISODE
0 HOME SLEEP EPISODE ADMISSION Waking MRI with PSG
1 SLEEP EPISODE ON CCI with PSG
2 Waking MRI with PSG
3 MRI DURING SLEEP EPISODE with PSG SLEEP EPISODE ON CCI DISCHARGE
• 1 week of pre-study sleep monitoring at home
• 4-day inpatient study at BWH Center for Clinical Investigation (CCI)
and MRI Research Center (BWMRC):
– Baseline waking MRI scan (BWMRC)
• T1, T2, FLAIR, DTI
– Baseline night of sleep (CCI)
– 36h “Constant Routine”: controlled sleep deprivation (CCI)
• Blood and saliva samples, cognitive-behavioral tests
– Waking scan after 36h awake (BWMRC)
• T1, T2, FLAIR, DTI
– Overnight scan during sleep (BWMRC)
• T1 time-series

14. Collection of Performance and Biospecimen Data at Intensive
Physiological Monitoring Unit, Harvard Catalyst Center for
Clinical Investigation, Brigham & Women’s Hospital

15. Collection of MRI and EEG data

16. Sleep Inside MRI Scanner
# OF EPOCHS 3651A 3667A 3701A 3728A 3740A 3744A 3752A 3771A 3775A 3783A
Total 684 817 652 627 278 776 737 700 724 746
WAKE 411 566 322 292 131 555 404 128 522 362
N1 65 160 118 150 24 81 195 43 73 97
N2 89 67 135 121 82 59 77 321 111 225
N3 52 22 32 24 24 26 21 175 14 60
REM 67 0 38 24 0 30 31 4 1 0
UNDEFINED 0 2 7 16 17 25 9 29 3 2

17. Results
10 healthy participants (18-25 years old)
Wake vs. Sleep
No significant differences in EPVS
Normal Wake vs. Sleep-deprived Wake
No significant differences in EPVS

18. Future Directions
• EPVS Volumetrics
• Voxel-based Analysis
• Different MRI Acquisition
– Diffusion MRI
– Contrast MRI

19. LONGITUDINAL
APP
PSEN-1
PSEN-2
Est. 2008 with the grant U19 AG032438 to Washington
University (PI: JC Morris) from the National Institute on
Aging (P50AG005681, P01AG003991, P01AG026276)
https://dian.wustl.edu

20. Alzheimer’s Disease Biomarkers
Jack et al. 2010

21. PET and CSF Biomarkers of Brain
Deposition of Beta-Amyloid and Tau
CSF Biomarkers of AD
 Beta-Amyloid
 Tau
PET with Pittsburgh Compound B

22. Results
Enlarged Perivascular Spaces
137 Mutation Carriers
Outcome Standardized Beta P-value
PET Amyloid – 0.17 0.03
CSF Amyloid 0.19 0.03
CSF Tau – 0.33 <0.001
General linear model adjusted for age, sex, cerebral white matter lesions
Glymphatic Clearance / Stasis

23. Conclusions & Future Directions
• Our findings support the presence of a
glymphatic mechanism of clearance in
humans
• Longitudinal study of the relationship
between EPVS and AD biomarkers

24. https://cni.bwh.harvard.edu