Acute Regression in Down Syndrome
Abstract
:1. Introduction
2. Materials and Methods
2.1. ABC-DS
2.2. Participants
2.3. Dependent Measures
3. Results
4. Discussion
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
- Rosso, M.; Fremion, E.; Santoro, S.L.; Dreskovic, N.M.; Chitnis, T.; Skotko, B.G.; Santoro, J.D. Down syndrome disintegrative disorder: A clinical regression syndrome of increasing importance. Pediatrics 2019, 1456, 2019–2939. [Google Scholar] [CrossRef]
- Walpert, M.; Holland, A.; Zaman, S. A systematic review of unexplained early regression in adolescents and adults with Down’s syndrome. Brain Sci. 2021. in submission. [Google Scholar]
- Devenny, D.; Matthews, A. Regression: Atypical loss of attained functioning in children and adolescents with Down syndrome. Int. J. Dev. Disabil. 2011, 41, 233–264. [Google Scholar]
- Mircher, C.; Cieuta-Walti, C.; Marey, I.; Rebillat, A.S.; Cretu, L.; Milenko, E.; Conte, M.; Sturtz, F.; Rethore, M.O.; Ravel, A. Acute regression in young people with Down syndrome. Brain Sci. 2017, 7, 57. [Google Scholar] [CrossRef]
- Ghazuiddin, N.; Nassiri, A.; Miles, J.H. Catatonia in Down syndrome; a treatable cause of regresson. Neuropsychiatr. Dis. Treat. 2015, 11, 941–949. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Santoro, S.L.; Cannon, S.; Capone, G. Unexplained regression in Down syndrome: 35 cases from an international Down syndrome database. Genet. Med. 2020, 22, 767–776. [Google Scholar] [CrossRef]
- Worley, G.; Crissman, B.G.; Cadogan, E.; Milleson, C.; Adkins, D.W. Down syndrome disintegrative disorder: New-onset autistic regression, dementia, and insomnia in older children and adolescents with Down syndrome. J. Child Neurol. 2015, 30, 1147–1152. [Google Scholar] [CrossRef]
- Akahoshi, K.; Matsuda, H.; Funahashi, M.; Hanaoka, T.; Suzuki, Y. Acute neuropsychiatric disorders in adolescents and young adults with Down syndrome: Japanese case reports. Neuropsychiatr. Dis. Treat. 2012, 8, 339–345. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Fortea, J.; Vilaplana, E.; Carmona-Iragui, M.; Benejam, B.; Videla, L.; Barroeta, I.; Fernández, S.; Altuna, M.; Pegueroles, J.; Montal, V.; et al. Clinical and biomarker changes of Alzheimer’s disease in adults with Down syndrome: A cross-sectional study. Lancet 2020, 395, 1988–1997. [Google Scholar] [CrossRef]
- Teipel, S.J.; Schapiro, M.B.; Alexander, G.E.; Krasuski, J.S.; Horwitz, B.; Hoehne, C.; Moller, H.J.; Rapoport, S.; Hampel, H. Relation of corpus callosum and hippocampal size to age in nondemented adults with Down’s syndrome. Am. J. Psychiatry 2003, 160, 1870–1878. [Google Scholar] [CrossRef] [PubMed]
- Wiseman, F.K.; Al-Janabi, T.; Hardy, J.; Karmiloff-Smith, A.; Nizetic, D.; Tybulewicz, V.L.; Fisher, E.M.; Strydom, A. A genetic cause of Alzheimer disease: Mechanistic insights from Down syndrome. Nat. Rev. Neurosci. 2015, 16, 564–574. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Zigman, W.B.; Devenny, D.A.; Krinsky-McHale, S.J.; Jenkins, E.C.; Urv, T.K.; Wegiel, J.; Schupf, N.; Silverman, W. Alzheimer’s disease in adults with Down syndrome. Int. Rev. Res. Ment. Retard. 2008, 36, 103–145. [Google Scholar] [PubMed] [Green Version]
- Fortea, J.; Carmona-Iragui, M.; Benejam, B.; Videla, L.; Barroeta, I.; Fernández, S.; Altuna, M.; Pegueroles, J.; Montal, V.; Valldeneu, S.; et al. Plasma and CSF biomarkers for the diagnosis of Alzheimer’s disease in adults with Down syndrome: A cross-sectional study. Lancet Neurol. 2018, 17, 860–869. [Google Scholar] [CrossRef]
- Iulita, M.F.; Ower, A.; Barone, C.; Pentz, R.; Gubert, P.; Romano, C.; Cantarella, R.A.; Elia, F.; Buono, S.; Recupero, M.; et al. An inflammatory and trophic disconnect biomarker profile revealed in Down syndrome plasma: Relation to cognitive decline and longitudinal evaluation. Alzheimer’s Dement. 2016, 12, 1132–1148. [Google Scholar] [CrossRef]
- Lee, N.C.; Yang, S.Y.; Chieh, J.J.; Huang, P.T.; Chang, L.M.; Chiu, Y.N.; Huang, A.C.; Chien, Y.H.; Hwu, W.L.; Chiu, M.J. Blood beta-amyloid and tau in down syndrome: A comparison with Alzheimer’s disease. Front Aging Neurosci. 2017, 8, 316. [Google Scholar] [CrossRef] [Green Version]
- Schupf, N.; Patel, B.; Pang, D.; Zigman, W.B.; Silverman, W.; Mehta, P.D.; Mayeux, R. Elevated plasma β-amyloid peptide Aβ42 levels, incident dementia, and mortality in Down syndrome. Arch. Neurol. 2007, 64, 1007–1013. [Google Scholar] [CrossRef] [Green Version]
- Coppus, A.M.; Schuur, M.; Vergeer, J.; Janssens, A.C.; Oostra, B.A.; Verbeek, M.M.; van Duijn, C.M. Plasma beta amyloid and the risk of Alzheimer’s disease in Down syndrome. Neurobiol. Aging 2012, 33, 1988–1994. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Head, E.; Doran, E.; Nistor, M.; Hill, M.; Schmitt, F.A.; Haier, R.J.; Lott, I.T. Plasma amyloid-beta as a function of age, level of intellectual disability, and presence of dementia in Down syndrome. J. Alzheimers Dis. 2011, 23, 399–409. [Google Scholar] [CrossRef]
- Tamaoka, A.; Sekijima, Y.; Matsuno, S.; Tokuda, T.; Shoji, S.; Ikeda, S.I. Amyloid beta protein species in cerebrospinal fluid and in brain from patients with Down’s syndrome. Ann. Neurol. 1999, 46, 933. [Google Scholar] [CrossRef]
- Tapiola, T.; Soininen, H.; Pirttila, T. CSF tau and Abeta42 levels in patients with Down’s syndrome. Neurology 2001, 56, 979–980. [Google Scholar] [CrossRef] [PubMed]
- Kasai, T.; Tatebe, H.; Kondo, M.; Ishii, R.; Ohmichi, T.; Yeung, W.T.E.; Morimoto, M.; Chiyonobu, T.; Terada, N.; Allsop, D.; et al. Increased levels of plasma total tau in adult Down syndrome. PLoS ONE 2017, 12, e0188802. [Google Scholar] [CrossRef] [Green Version]
- Petersen, M.E.; Rafii, M.S.; Julovich, D.; Zhang, F.; Hall, J.; Ances, B.M.; Schupf, N.; Krinsky-McHale, S.J.; Mapstone, M.; Silverman, W.; et al. Plasma total-tau and neurofilament light chain as diagnostic biomarkers of Alzheimer’s disease dementia and mild cognitive impairment in adults with Down syndrome. Alzheimer’s Dement. Diagn. Assess. Dis. Monit. 2021, 79, 671–681. [Google Scholar]
- Strydom, A.; Heslegrave, A.; Startin, C.M.; Mok, K.Y.; Hardy, J.; Groet, J.; Nizetic, D.; Zetterberg, H.; LonDownS Consortium. Neurofilament light as a blood biomarker for neurodegeneration in Down syndrome. Alzheimer’s Res Ther. 2018, 10, 39. [Google Scholar] [CrossRef]
- Koran, M.E.; Hohman, T.J.; Edwards, C.M.; Vega, J.N.; Pryweller, J.R.; Slosky, L.E.; Crockett, G.; de Rey, L.V.; Meds, S.A.; Danker, N.; et al. Differences in age-related effects on brain volume in Down syndrome as compared to Williams’ syndrome and typical development. J. Neurodev. Disord. 2014, 6, 1–11. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Dunn, L.M.; Dunn, D.M. Peabody Picture Vocabulary, 4th ed.; NCD Pearson, Inc.: San Antonio, TX, USA, 2007. [Google Scholar]
- Handen, B.L.; Lott, I.T.; Christian, B.; Schupf, N.; O’Bryant, S.; Mapstone, M.; Fagan, A.M.; Lee, J.; Tudorascu, D.; Wang, M.; et al. The Alzheimer’s Biomarker Consortium-Down Syndrome (ABC-DS): Rationale and methodology. Alzheimer’s Dement. Diagn. Assess. Dis. Monit. 2020, 12, 1–15. [Google Scholar]
- Klunk, W.E.; Koeppe, R.A.; Price, J.C.; Benzinger, T.L.; Devous, M.D.; Jagust, W.J.; Johnson, K.A.; Mathis, C.A.; Minhas, D.; Pontecorvo, M.J.; et al. The Centiloid Project: Standardizing quantitative amyloid plaque estimation by PET. Alzheimers 2015, 11, 1–15. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Knopman, D.S.; Lundt, E.S.; Therneau, T.M.; Albertson, S.M.; Gunter, J.L.; Senjem, M.L.; Schwarz, C.G.; Mielke, M.M.; Machulda, M.M.; Alzheimer’s Dis Neuroimaging Initiative; et al. Association of Initial beta-Amyloid Levels with Subsequent Flortaucipir Positron Emission Tomography Changes in Persons Without Cognitive Impairment. JAMA Neurol. 2021, 78, 217–228. [Google Scholar] [CrossRef]
- Svarer, C.; Madsen, K.; Hasselbalch, S.G.; Pinborg, L.H.; Haugbol, S.; Frokjaer, V.G.; Holm, S.; Paulson, O.B.; Knudsen, G.M. MR-based automatic delineation of volumes of interest in human brain PET images using probability maps. Neuroimage 2005, 24, 969–979. [Google Scholar] [CrossRef] [PubMed]
- Desikan, R.S.; Ségonne, F.; Fischl, B.; Quinn, B.T.; Dickerson, B.C.; Blacker, D.; Buckner, R.L.; Dale, A.M.; Maguire, R.P.; Hyman, B.T.; et al. An automated labeling system for subdividing the human cerebral cortex on MRI scans into gyral based regions of interest. Neuroimage 2006, 31, 968–980. [Google Scholar] [CrossRef]
- Braak, H.; Braak, E. Neuropathological staging of alzheimer-related changes. Acta Neuropathol. 1991, 82, 239–259. [Google Scholar] [CrossRef]
- Scholl, M.; Lockhart, S.N.; Schonhaut, D.R.; O’Neil, J.P.; Janabi, M.; Ossenkoppele, R.; Baker, S.L.; Vogel, J.W.; Faria, J.; Schwimmer, H.D.; et al. PET Imaging of Tau Deposition in the Aging Human Brain. Neuron 2016, 89, 971–982. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Aylward, E.H.; Li, Q.; Honeycutt, N.A.; Warren, A.C.; Pulsifer, M.B.; Barta, P.E.; Chan, M.D.; Smith, P.D.; Jerram, M.; Pearlson, G. MRI volumes of the hippocampus and amygdala in adults with Down’s syndrome with and without dementia. Am. J. Psychiatry 1999, 156, 564–568. [Google Scholar] [PubMed]
- Hartley, S.L.; Handen, B.L.; Devenny, D.A.; Hardison, R.; Mihaila, I.; Price, J.C.; Cohen, A.D.; Klunk, W.E.; Mailick, M.R.; Johnson, S.C.; et al. Cognitive functioning in relation to the accumulation of brain β-amyloid in healthy adults with Down syndrome. Brain 2014, 137, 2556–2563. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Montal, V.; Vilaplana, E.; Peguerloes, J.; Bejanin, A.; Alcolea, D.; Carmona-Iragui, M.; Clarimón, J.; Levin, J.; Cruchaga, C.; Graff-Radford, N.R.; et al. Biphasic cortical macro- and microstructural changes in autosomal Alzheimer’s disease. Alzheimers 2021, 17, 618–628. [Google Scholar] [CrossRef] [PubMed]
- Vilaplana, E.; Rodriguez-Vieitz, E.; Ferreira, D.; Montal, V.; Almkvist, O.; Wall, A.; Lleó, A.; Westman, E.; Graff, C.; Fortea, J.; et al. Cortical microstructural correlates of astrocytosis in autosomal-dominant Alzheimer disease. Neurology 2020, 94, e2026–e2036. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Annus, T.; Wilson, L.R.; Acosta-Cabronero, J.; Cardenas-Blanco, A.; Hong, Y.T.; Fryer, T.D.; Coles, J.P.; Menon, D.K.; Zaman, S.H.; Holland, A.J.; et al. The Down syndrome brain in the presence and absence of fibrillar β-amyloidosis. Neurobiology 2017, 53, 11–19. [Google Scholar] [CrossRef]
- Lao, P.J.; Handen, B.L.; Betthauser, T.J.; Mihaila, I.; Hartley, S.L.; Cohen, A.D.; Tudorascu, D.L.; Bulova, P.D.; Lopresti, B.J.; Tumuluru, R.V.; et al. Longitudinal changes in amyloid PET and volumetric MRI in the non-demented Down syndrome population. Alzheimer’s Dement. Diagn. Assess. Dis. Monit. 2017, 9, 1–9. [Google Scholar]
- Petersen, M.E.; Zhang, F.; Schupf, N.; Krinsky-McHale, S.J.; Hall, J.; Mapstone, M.; Cheema, A.; Silverman, W.; Lott, I.T.; Rafii, M.S.; et al. Proteomic Profiles for Alzheimer’s Disease and Mild Cognitive Impairment Among Adults with Down Syndrome Spanning Serum and Plasma: An ABC-DS Study. the Alzheimer’s Biomarker Consortium—Down Syndrome (ABC-DS). Alzheimer’s Dement. Diagn. Assess. Dis. Monit. 2020, 12, 1–11. [Google Scholar] [CrossRef]
Part | Sex | Current Age | Current IQ/MA | ApoE Status | Age at Regression | Description of Regression |
---|---|---|---|---|---|---|
01 | M | 33 | 6 years 5 months | E3/E3 | 28 | Individual had some loss of functioning, primarily deterioration in verbal skills and increased irritability. They were given a diagnosis of early dementia at the time. Some improvement occurred over the following 2 years, although not to previous levels of functioning. Dementia diagnosis was subsequently removed. |
02 | F | 44 | 4 years 0 months | E3/E3 | 27–28 | Individual used to have a part-time job and spoke fluently. After regression, was unable to perform her job and no longer traveled independently. b They also lost interest in most activities and stopped keeping up with friends. No diagnosis of dementia was made. There has been gradual improvement since that time, although not to previous levels of functioning. |
03 | F | 36 | 3 years 8 months | E3/E3 | Mid 20s | Individual was given a dementia diagnosis approximately 10 years ago following a rapid decline in functioning. They were prescribed donepezil and improved a little. The dementia diagnosis was subsequently removed. They continued to improve after medication was discontinued but did not return to prior levels of functioning. |
04 | M | 54 | 3 years 1 mon. | E4/E3 | Early 20s. | Individual had a significant loss of functioning in their early 20s. Prior to regression they were highly verbal and independent. Subsequently, they were unable to talk, complete basic self-care activities, or participate in work and social activities. They were diagnosed with depression and prescribed an SSRI. There was some minimal improvement in language subsequently noted along with some improvement in self-care and social skills. They have maintained this same level of functioning since then and continue to have a diagnosis of depression and to take medication. They were never officially diagnosed with regression. |
05 | F | 28 | <2 years 0 months | E3/E3 | Mid 20s | Individual evidenced significant loss of skills in early 20s and was diagnosed with dementia. Some small gains have been noted since that time, but not to prior levels of functioning. The dementia diagnosis was removed, however, significant behavioral issues continue along with limited language. |
Variable | Regression Group | Matched Group 1:15 |
---|---|---|
Age [Mean (SD)/N(%)] | 38.06 (8.78) | 38.01 (8.06) |
Mental Age | 3.42 (2.30) | 8.16 (4.40) |
Sex (Male) | 2 (40%) | 6 (40%) |
ApoE Allele * | 1 (20%) | 3 (20%) |
Karyotype | ||
Full Trisomy 21 | 4 (80%) | 12 (80%) |
Partial Trisomy | 1 (20%) | 3 (20%) |
Cognitive Level | ||
Mild | 0 (0%) | 4 (26.7%) |
Moderate | 3 (60%) | 11 (73.3%) |
Severe | 2(40%) | 0 (0%) |
Consensus Diagnosis | ||
Cognitively Stable | 4 (80.0%) | 13 (86.7%) |
Unable to Determine | 1 (20.0%) | 2 (13.3%) |
Regress. Group (N) | Mean (SD) | Median | Matched Group 1:15 (N) | Mean (SD) | Median | |
---|---|---|---|---|---|---|
MRI Scan | ||||||
Hippocampal Volume | ||||||
Left | 4 | 3625.3 (283.8) | 3618.4 | 11 | 3174.7 (435.2) | 3163.2 |
Right | 4 | 3655.1 (299.2) | 3653.3 | 11 | 3156.3 (498.0) | 3120.9 |
Hippocampal Thickness | 4 | 3.00 (0.11) | 2.98 | 11 | 2.95 (0.21) | 2.86 |
Caudate | ||||||
Left | 4 | 3471.6 (415.4) | 3372.6 | 11 | 3219.0 (579.6) | 3256.4 |
Right | 4 | 3505.3 (475.5) | 3447.4 | 11 | 3310.7 (375.8) | 3352.0 |
Putamen | ||||||
Left | 4 | 6205.7 (453.7) | 6375.3 | 11 | 5408.4 (748.4) | 5149.4 |
Right | 4 | 6031.2 (356.6) | 5903.3 | 11 | 5523.5 (578.2) | 5300.0 |
Amyloid PET | ||||||
Centiloid SUVR | 5 | 17.77 (22.09) | 6.37 | 15 | 20.70 (22.59) | 18.66 |
Amyloid Negative ≤ 22 | 3 (60%) | 9 (60%) | ||||
Amyloid Positive >= 22 | 2 (40%) | 6 (40%) | ||||
TAU PET | ||||||
Braak 1 | 4 | 1.22 (0.16) | 1.20 | 15 | 1.19 (0.19) | 1.14 |
Braak 2 | 4 | 1.17 (0.26) | 1.12 | 15 | 1.18 (0.17) | 1.11 |
Braak 3 | 4 | 1.11 (0.09) | 1.09 | 15 | 1.13 (0.14) | 1.09 |
Braak 4 | 4 | 1.08 (0.08) | 1.10 | 15 | 1.11 (0.12) | 1.08 |
Braak 5 | 4 | 1.08 (0.04) | 1.10 | 15 | 1.09 (0.13) | 1.07 |
Braak 6 | 4 | 1.06 (0.04) | 1.08 | 15 | 1.03 (0.07) | 1.02 |
Plasma | ||||||
Aβ40 pg/mL | 4 | 413.25 (52.51) | 403 | 14 | 452.43 (86.48) | 452 |
Aβ42 pg/mL | 4 | 15.13 (2.89) | 14.60 | 14 | 15.81 (3.37) | 15.60 |
Aβ40/ Aβ42 ratio | 4 | 27.64 (2.93) | 27.43 | 14 | 29.06 (4.34) | 29.25 |
NfL pg/mL | 5 | 18.23 (11.37) | 15.20 | 15 | 11.49 (6.51) | 10.80 |
Total Tau pg/mL | 4 | 6.13 (6.55) | 3.26 | 14 | 3.72 (4.09) | 2.68 |
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. |
© 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
Share and Cite
Handen, B.; Clare, I.; Laymon, C.; Petersen, M.; Zaman, S.; O'Bryant, S.; Minhas, D.; Tudorascu, D.; Brown, S.; Christian, B., on behalf of the Alzheimer’s Biomarker Consortium-Down Syndrome (ABC-DS). Acute Regression in Down Syndrome. Brain Sci. 2021, 11, 1109. https://doi.org/10.3390/brainsci11081109
Handen B, Clare I, Laymon C, Petersen M, Zaman S, O'Bryant S, Minhas D, Tudorascu D, Brown S, Christian B on behalf of the Alzheimer’s Biomarker Consortium-Down Syndrome (ABC-DS). Acute Regression in Down Syndrome. Brain Sciences. 2021; 11(8):1109. https://doi.org/10.3390/brainsci11081109
Chicago/Turabian StyleHanden, Benjamin, Isabel Clare, Charles Laymon, Melissa Petersen, Shahid Zaman, Sid O'Bryant, Davneet Minhas, Dana Tudorascu, Stephanie Brown, and Bradley Christian on behalf of the Alzheimer’s Biomarker Consortium-Down Syndrome (ABC-DS). 2021. "Acute Regression in Down Syndrome" Brain Sciences 11, no. 8: 1109. https://doi.org/10.3390/brainsci11081109
APA StyleHanden, B., Clare, I., Laymon, C., Petersen, M., Zaman, S., O'Bryant, S., Minhas, D., Tudorascu, D., Brown, S., & Christian, B., on behalf of the Alzheimer’s Biomarker Consortium-Down Syndrome (ABC-DS). (2021). Acute Regression in Down Syndrome. Brain Sciences, 11(8), 1109. https://doi.org/10.3390/brainsci11081109