Reduced brain amyloid burden in elderly patients with narcolepsy type 1
Audrey Gabelle MD
Memory Research and Resources Center, Department of Neurology, Gui de Chauliac University Hospital Center
University of Montpellier
National Institute of Health and Medical Research U1061, Neuropsychiatry: Epidemiological and Clinical Research
Search for more papers by this authorIsabelle Jaussent MD
University of Montpellier
National Institute of Health and Medical Research U1061, Neuropsychiatry: Epidemiological and Clinical Research
Search for more papers by this authorFayçal Ben Bouallègue MD
University of Montpellier
Department of Nuclear Medicine, Montpellier University Hospital
PhyMedExp, National Institute of Health and Medical Research, National Center for Scientific Research
Search for more papers by this authorSylvain Lehmann MD
University of Montpellier
National Institute of Health and Medical Research U1183, Saint Eloi Hospital
Search for more papers by this authorRégis Lopez MD
University of Montpellier
National Institute of Health and Medical Research U1061, Neuropsychiatry: Epidemiological and Clinical Research
Narcolepsy National Reference Center, Sleep Center, Department of Neurology, Montpellier University Hospital Center, Montpellier, France
Search for more papers by this authorLucie Barateau MD
University of Montpellier
National Institute of Health and Medical Research U1061, Neuropsychiatry: Epidemiological and Clinical Research
Narcolepsy National Reference Center, Sleep Center, Department of Neurology, Montpellier University Hospital Center, Montpellier, France
Search for more papers by this authorCaroline Grasselli MSc
Memory Research and Resources Center, Department of Neurology, Gui de Chauliac University Hospital Center
Search for more papers by this authorCarole Pesenti MSc
Narcolepsy National Reference Center, Sleep Center, Department of Neurology, Montpellier University Hospital Center, Montpellier, France
Search for more papers by this authorDelphine de Verbizier MD
Department of Nuclear Medicine, Montpellier University Hospital
Search for more papers by this authorSéverine Béziat MSc
University of Montpellier
National Institute of Health and Medical Research U1061, Neuropsychiatry: Epidemiological and Clinical Research
Search for more papers by this authorDenis Mariano-Goulart MD
University of Montpellier
Department of Nuclear Medicine, Montpellier University Hospital
PhyMedExp, National Institute of Health and Medical Research, National Center for Scientific Research
Search for more papers by this authorBertrand Carlander MD
Narcolepsy National Reference Center, Sleep Center, Department of Neurology, Montpellier University Hospital Center, Montpellier, France
Search for more papers by this authorCorresponding Author
Yves Dauvilliers MD
University of Montpellier
National Institute of Health and Medical Research U1061, Neuropsychiatry: Epidemiological and Clinical Research
Narcolepsy National Reference Center, Sleep Center, Department of Neurology, Montpellier University Hospital Center, Montpellier, France
Address correspondence to Dr Dauvilliers, Narcolepsy National Reference Center, Sleep Center, Department of Neurology, CHU Montpellier, University of Montpellier, Montpellier, France. E-mail: [email protected]Search for more papers by this authorthe Alzheimer's Disease Neuroimaging Initiative
Search for more papers by this authorMulti-Domain Intervention Alzheimer's Prevention Trial study groups
Search for more papers by this authorAudrey Gabelle MD
Memory Research and Resources Center, Department of Neurology, Gui de Chauliac University Hospital Center
University of Montpellier
National Institute of Health and Medical Research U1061, Neuropsychiatry: Epidemiological and Clinical Research
Search for more papers by this authorIsabelle Jaussent MD
University of Montpellier
National Institute of Health and Medical Research U1061, Neuropsychiatry: Epidemiological and Clinical Research
Search for more papers by this authorFayçal Ben Bouallègue MD
University of Montpellier
Department of Nuclear Medicine, Montpellier University Hospital
PhyMedExp, National Institute of Health and Medical Research, National Center for Scientific Research
Search for more papers by this authorSylvain Lehmann MD
University of Montpellier
National Institute of Health and Medical Research U1183, Saint Eloi Hospital
Search for more papers by this authorRégis Lopez MD
University of Montpellier
National Institute of Health and Medical Research U1061, Neuropsychiatry: Epidemiological and Clinical Research
Narcolepsy National Reference Center, Sleep Center, Department of Neurology, Montpellier University Hospital Center, Montpellier, France
Search for more papers by this authorLucie Barateau MD
University of Montpellier
National Institute of Health and Medical Research U1061, Neuropsychiatry: Epidemiological and Clinical Research
Narcolepsy National Reference Center, Sleep Center, Department of Neurology, Montpellier University Hospital Center, Montpellier, France
Search for more papers by this authorCaroline Grasselli MSc
Memory Research and Resources Center, Department of Neurology, Gui de Chauliac University Hospital Center
Search for more papers by this authorCarole Pesenti MSc
Narcolepsy National Reference Center, Sleep Center, Department of Neurology, Montpellier University Hospital Center, Montpellier, France
Search for more papers by this authorDelphine de Verbizier MD
Department of Nuclear Medicine, Montpellier University Hospital
Search for more papers by this authorSéverine Béziat MSc
University of Montpellier
National Institute of Health and Medical Research U1061, Neuropsychiatry: Epidemiological and Clinical Research
Search for more papers by this authorDenis Mariano-Goulart MD
University of Montpellier
Department of Nuclear Medicine, Montpellier University Hospital
PhyMedExp, National Institute of Health and Medical Research, National Center for Scientific Research
Search for more papers by this authorBertrand Carlander MD
Narcolepsy National Reference Center, Sleep Center, Department of Neurology, Montpellier University Hospital Center, Montpellier, France
Search for more papers by this authorCorresponding Author
Yves Dauvilliers MD
University of Montpellier
National Institute of Health and Medical Research U1061, Neuropsychiatry: Epidemiological and Clinical Research
Narcolepsy National Reference Center, Sleep Center, Department of Neurology, Montpellier University Hospital Center, Montpellier, France
Address correspondence to Dr Dauvilliers, Narcolepsy National Reference Center, Sleep Center, Department of Neurology, CHU Montpellier, University of Montpellier, Montpellier, France. E-mail: [email protected]Search for more papers by this authorthe Alzheimer's Disease Neuroimaging Initiative
Search for more papers by this authorMulti-Domain Intervention Alzheimer's Prevention Trial study groups
Search for more papers by this authorMembers of the Multi-Domain Intervention Alzheimer's Prevention Trial study group are available as an online supplementary file.
Abstract
Objective
To determine whether brain amyloid burden in elderly patients with narcolepsy type 1 (NT1) is lower than in controls, and to assess in patients with NT1 the relationships between amyloid burden, cerebral spinal fluid (CSF) markers of Alzheimer disease (AD), CSF orexin-A, and cognitive profile.
Methods
Cognitive and 18F-florbetapir positron emission tomography (PET) data were compared in patients with NT1 aged ≥ 65 years (n = 23) and in age- and sex-matched controls free of clinical dementia selected from the Alzheimer's Disease Neuroimaging Initiative (ADNI; n = 69) and the Multi-Domain Intervention Alzheimer's Prevention Trial (MAPT-18F AV45-PET; n = 23) cohorts. The standardized uptake values (SUVs) of the cortical retention index for 6 regions of interest were computed and averaged to create a mean SUV ratio normalized to 3 subcortical reference regions (cerebellum, pons, and a composite region). A cortical/cerebellum SUV ratio ≥ 1.17 defined positive PET amyloid.
Results
Lower cortical amyloid burden was observed in the NT1 than in the ADNI and MAPT-AV45 groups (mean cortical/cerebellum SUV ratios = 0.95 ± 0.15, 1.11 ± 0.18 [p < 0.0001], and 1.14 ± 0.17 [p = 0.0005], respectively). Similar results were obtained with all subcortical reference regions and for all cortical regions of interest, except cingulum. Only 1 patient with NT1 (4.4%) had positive PET amyloid compared with 27.5% in the ADNI and 30.4% in the MAPT-AV45 group. In the NT1 group, cortical or regional amyloid load was not associated with CSF orexin-A, CSF AD biomarkers, or neuropsychological profile.
Interpretation
Lower brain amyloid burden, assessed by 18F-florbetapir PET, in patients with NT1 suggests delayed appearance of amyloid plaques. ANN NEUROL 2019;85:74–83.
Potential Conflicts of Interest
Nothing to report.
References
- 1Frisoni GB, Lorenzi M, Caroli A, et al. In vivo mapping of amyloid toxicity in Alzheimer disease. Neurology 2009; 72: 1504–1511.
- 2Jack CR Jr, Knopman DS, Jagust WJ, et al. Hypothetical model of dynamic biomarkers of the Alzheimer's pathological cascade. Lancet Neurology 2010; 9: 119–128.
- 3Bateman RJ, Xiong C, Benzinger TL, et al. Clinical and biomarker changes in dominantly inherited Alzheimer's disease. N Engl J Med 2012; 367: 795–804.
- 4McDade E, Bateman RJ. Stop Alzheimer's before it starts. Nature 2017; 547: 153–155.
- 5Peng W, Achariyar TM, Li B, et al. Suppression of glymphatic fluid transport in a mouse model of Alzheimer's disease. Neurobiol Dis 2016; 93: 215–225.
- 6Jessen NA, Munk AS, Lundgaard I, Nedergaard M. The glymphatic system: a beginner's guide. Neurochem Res 2015; 40: 2583–2599.
- 7Tarasoff-Conway JM, Carare RO, Osorio RS, et al. Clearance systems in the brain—implications for Alzheimer disease. Nat Rev Neurol 2015; 11: 457–470.
- 8Kang JE, Lim MM, Bateman RJ, et al. Amyloid-beta dynamics are regulated by orexin and the sleep-wake cycle. Science 2009; 326: 1005–1007.
- 9Roh JH, Jiang H, Finn MB, et al. Potential role of orexin and sleep modulation in the pathogenesis of Alzheimer's disease. J Exp Med 2014; 211: 2487–2496.
- 10Fronczek R, van Geest S, Frolich M, et al. Hypocretin (orexin) loss in Alzheimer's disease. Neurobiol Aging 2012; 33: 1642–1650.
- 11Dauvilliers YA, Lehmann S, Jaussent I, Gabelle A. Hypocretin and brain beta-amyloid peptide interactions in cognitive disorders and narcolepsy. Front Aging Neurosci 2014; 6: 119.
- 12Wennstrom M, Londos E, Minthon L, Nielsen HM. Altered CSF orexin and alpha-synuclein levels in dementia patients. J Alzheimers Dis 2012; 29: 125–132.
- 13Liguori C, Romigi A, Nuccetelli M, et al. Orexinergic system dysregulation, sleep impairment, and cognitive decline in Alzheimer disease. JAMA Neurol 2014; 71: 1498–1505.
- 14Ju YS, Ooms SJ, Sutphen C, et al. Slow wave sleep disruption increases cerebrospinal fluid amyloid-beta levels. Brain 2017; 140: 2104–2111.
- 15Shan L, Dauvilliers Y, Siegel JM. Interactions of the histamine and hypocretin systems in CNS disorders. Nat Rev Neurol 2015; 11: 401–413.
- 16Scammell TE. Narcolepsy. N Engl J Med 2015; 373: 2654–2662.
- 17Dauvilliers Y, Montplaisir J, Molinari N, et al. Age at onset of narcolepsy in two large populations of patients in France and Quebec. Neurology 2001; 57: 2029–2033.
- 18Scammell TE, Matheson JK, Honda M, et al. Coexistence of narcolepsy and Alzheimer's disease. Neurobiol Aging 2012; 33: 1318–1319.
- 19 American Academy of Sleep Medicine. International classification of sleep disorders-third edition (ICSD-3). Darien, IL: American Academy of Sleep Medicine, 2014.
- 20Johns MW. A new method for measuring daytime sleepiness: the Epworth Sleepiness Scale. Sleep 1991; 14: 540–545.
- 21Beck AT, Ward CH, Mendelson M, et al. An inventory for measuring depression. Arch Gen Psychiatry 1961; 4: 561–571.
- 22Rabin R, de Charro F. EQ-5D: a measure of health status from the EuroQol Group. Ann Med 2001; 33: 337–343.
- 23Hughes CP, Berg L, Danziger WL, et al. A new clinical scale for the staging of dementia. Br J Psychiatry 1982; 140: 566–572.
- 24Saykin AJ, Wishart HA, Rabin LA, et al. Older adults with cognitive complaints show brain atrophy similar to that of amnestic MCI. Neurology 2006; 67: 834–842.
- 25Vellas B, Carrie I, Gillette-Guyonnet S, et al. MAPT study: a multidomain approach for preventing Alzheimer's disease: design and baseline data. J Prev Alzheimers Dis 2014; 1: 13–22.
- 26Joshi AD, Pontecorvo MJ, Clark CM, et al. Performance characteristics of amyloid PET with florbetapir F 18 in patients with Alzheimer's disease and cognitively normal subjects. J Nucl Med 2012; 53: 378–384.
- 27Joshi AD, Koeppe RA, Fessler JA, Kilbourn MR. Signal separation and parameter estimation in noninvasive dual-tracer PET scans using reference-region approaches. J Cereb Blood Flow Metab 2009; 29: 1346–1357.
- 28Schreiber S, Landau SM, Fero A, et al. Comparison of visual and quantitative florbetapir F 18 positron emission tomography analysis in predicting mild cognitive impairment outcomes. JAMA Neurol 2015; 72: 1183–1190.
- 29Payoux P, Delrieu J, Gallini A, et al. Cognitive and functional patterns of nondemented subjects with equivocal visual amyloid PET findings. Eur J Nucl Med Mol Imaging 2015; 42: 1459–1468.
- 30Dumurgier J, Vercruysse O, Paquet C, et al. Intersite variability of CSF Alzheimer's disease biomarkers in clinical setting. Alzheimers Dement 2013; 9: 406–413.
- 31Clark CM, Schneider JA, Bedell BJ, et al. Use of florbetapir-PET for imaging beta-amyloid pathology. JAMA 2011; 305: 275–283.
- 32Pontecorvo MJ, Mintun MA. PET amyloid imaging as a tool for early diagnosis and identifying patients at risk for progression to Alzheimer's disease. Alzheimers Res Ther 2011; 3: 11.
- 33Aizenstein HJ, Nebes RD, Saxton JA, et al. Frequent amyloid deposition without significant cognitive impairment among the elderly. Arch Neurol 2008; 65: 1509–1517.
- 34Bayard S, Croisier Langenier M, Cochen De Cock V, et al. Executive control of attention in narcolepsy. PLoS One 2012; 7: e33525.
- 35Heier MS, Skinningsrud A, Paus E, Gautvik KM. Increased cerebrospinal fluid levels of nerve cell biomarkers in narcolepsy with cataplexy. Sleep Med 2014; 15: 614–618.
- 36Kallweit U, Hidalgo H, Engel A, et al. Post H1N1 vaccination narcolepsy-cataplexy with decreased CSF beta-amyloid. Sleep Med 2012; 13: 323.
- 37Liguori C, Placidi F, Albanese M, et al. CSF beta-amyloid levels are altered in narcolepsy: a link with the inflammatory hypothesis? J Sleep Res 2014; 23: 420–424.
- 38Liguori C, Placidi F, Izzi F, et al. Beta-amyloid and phosphorylated tau metabolism changes in narcolepsy over time. Sleep Breath 2016; 20: 277–283; discussion 283.
- 39Jørgen Jennum P, Østergaard Pedersen L, Czarna Bahl JM, et al. Cerebrospinal fluid biomarkers of neurodegeneration are decreased or normal in narcolepsy. Sleep 2017; 40(1).
- 40Liguori C, Placidi F, Izzi F, et al. May CSF beta-amyloid and tau proteins levels be influenced by long treatment duration and stable medication in narcolepsy? Sleep Med 2014; 15: 1424.
- 41Slats D, Claassen JA, Verbeek MM, Overeem S. Reciprocal interactions between sleep, circadian rhythms and Alzheimer's disease: focus on the role of hypocretin and melatonin. Ageing Res Rev 2013; 12: 188–200.
- 42Gabelle A, Jaussent I, Hirtz C, et al. Cerebrospinal fluid levels of orexin-A and histamine, and sleep profile within the Alzheimer process. Neurobiol Aging 2017; 53: 59–66.
- 43Schmidt FM, Kratzsch J, Gertz HJ, et al. Cerebrospinal fluid melanin-concentrating hormone (MCH) and hypocretin-1 (HCRT-1, orexin-A) in Alzheimer's disease. PLoS One 2013; 8: e63136.
- 44Mattsson N, Insel PS, Donohue M, et al. Independent information from cerebrospinal fluid amyloid-beta and florbetapir imaging in Alzheimer's disease. Brain 2015; 138(pt 3): 772–783.
- 45Palmqvist S, Mattsson N, Hansson O. Cerebrospinal fluid analysis detects cerebral amyloid-beta accumulation earlier than positron emission tomography. Brain 2016; 139(pt 4): 1226–1236.
- 46Doraiswamy PM, Sperling RA, Johnson K, et al. Florbetapir F 18 amyloid PET and 36-month cognitive decline: a prospective multicenter study. Mol Psychiatry 2014; 19: 1044–1051.
- 47Sevigny J, Suhy J, Chiao P, et al. Amyloid PET screening for enrichment of early-stage Alzheimer disease clinical trials: experience in a phase 1b clinical trial. Alzheimer Dis Assoc Disord 2016; 30: 1–7.
- 48Landau SM, Horng A, Fero A et al. Amyloid negativity in patients with clinically diagnosed Alzheimer disease and MCI. Neurology 2016; 86: 1377–1385.
Citing Literature
