**1. Introduction**

There has been growing interest over the past decade in acute regression among adolescents and young adults with Down syndrome (DS) [1,2]. Characterized by a sudden, and often unexplained, reduction in expressive language, decreased functional living skills and reduced psychomotor activity; regression can result in a significant change in the long-term needs and independence of these individuals. Recent studies have identified a number of potential triggers and associations for regression, including medical issues (e.g., surgery, Hashimoto's disease, sleep apnea, sleep disruption, menarche and hormonal cycles, depression) and psychosocial stressors (e.g., transition from school, change in living arrangement) [3,4]. However, it is not understood why certain individuals with DS are at risk for regression in response to such events while the vast majority are able to cope effectively. Acute regression is reported to occur in up to 16% of individuals with DS [5] and has also been referred to by a number of other terms, including "new onset autism regression", "regression, dementia and insomnia", "catatonia" and "down syndrome degenerative disorder" [6,7]. The disorder appears to occur during adolescence through the mid 20s and can either be sudden onset or progressive.

**Citation:** 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

Academic Editor: Margaret B. Pulsifer

Received: 17 July 2021 Accepted: 13 August 2021 Published: 23 August 2021

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**Copyright:** © 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/).

Case reports and longitudinal studies of individuals with DS who have experienced acute regression indicate that only about 10% completely regain prior levels of functioning. Approximately 40% improve to some degree, but often fail to regain prior communication skill levels. The remainder fails to regain the skills that were lost [4]. Mircher and colleagues [4] present some of the most recent data on this disorder, describing a cohort of 30 adolescents and young adults with DS who experienced acute regression. In terms of clinical presentation, the most frequently reported psychiatric symptoms included mood disorders (30%), apathy, extreme slowness or catatonia (37%) and stereotypies (27%). Forty percent of the cohort displayed self- or other-directed aggressive behavior. Speech impairment occurred among almost the entire cohort (94%). Structural MRI scans were available for 15 patients and were found to be normal in 11 individuals. The only abnormalities noted were brain atrophy (*n* = 2) and hippocampal abnormalities (*n* = 2). In 2012, Akaloshi et al. [8] described a cohort of 13 adolescents/young adults (mean age 21.2 years) that were diagnosed with acute regression in Japan. All underwent MRI or CT scanning at the time of diagnosis and were treated and followed by the authors. Five of the 13 cases exhibited MRI or CT results that were suggestive of dementia, including mild cerebral white matter ischemia, hippocampal atrophy and basal ganglia calcification. However, similar to the data presented by Mircher et al. [4], no control scans (either of non-affected individuals with DS or neurotypical individuals) were included for comparison. In addition, many of the differences on the MRI and CT scans occur among individuals with DS in the absence of regression, and hippocampal abnormalities, in particular, have been previously documented in the DS population in comparison to neurotypical individuals [9,10]. Following a range of pharmacologic interventions, 23% of the Akaloshi et al. [8] cohort were subsequently rated as "improved", 54% as "partially improved" and 23% as "no difference".

Based upon the presentation and loss of skills, some investigators have proposed that regression in DS might be related to dementia [7]. In fact, it is not unusual for individuals with DS who experience acute regression to be given a diagnosis of Alzheimer's disease (AD) or dementia, based upon the symptom presentation and loss of skills. Consequently, practitioners may prescribe drugs, such as cholinesterase inhibitors (e.g., donepezil), which are commonly used to prevent memory loss in neurotypical adults with dementia. Actually, adults with DS are at significant risk for the development of AD, with most individuals with DS displaying the neuropathology associated with AD by 40 years of age [11,12]. This is thought to be due in large part to the presence of a third APP gene on the 21st chromosome, resulting in the accelerated production of β-amyloid (referred to as "amyloid") throughout the lifetime. Amyloid and amyloid plaques are believed to be key to initiating a cascade of subsequent events, including the hyperphosphorylation and accumulation of neurofibrillary tangles comprised of tau protein, as well as changes in brain structure and functioning (e.g., decreased grey matter density, decreased hippocampal volume, increased white matter hyperintensities) that lead to dementia.

Blood based biomarkers of amyloid peptides (amyloid beta [Aβ 40, 42]) have also been increasingly explored in adults with DS due in part to the early accumulation of this protein. Findings among those with DS and AD have been mixed, with some studies reporting elevations in Aβ 1–42 [13–16] and Aβ 1–40 [13,14,17,18] while others reporting a relative decrease [15,17,18] in levels, which corresponds with CSF findings [19,20]. Lower levels have also been noted among prodromal AD groups in comparison to healthy controls [13]. In contrast, other plasma biomarkers of AD pathology, including tauopathy (total tau) and neurodegeneration (neurofilament light chain [NfL]), have shown more consistent findings, with elevations seen among individuals with DS who have been diagnosed with AD (DS-AD) [13,15,21–23].

Finally, there is evidence of even earlier pathological changes in DS, such as increased levels of non-fibrillated amyloid in the teenage years along with non-developmental grey matter and ventricular changes [24]. However, while the symptoms of acute regression appear to mirror some of those of dementia, they differ in that they tend to be sudden rather than gradual and also are not followed by a subsequent and continued loss of skills over a 2–5 year period. Yet, it is also possible that some of the early pathological changes that are documented in adolescents and adults with DS who experience regression, might continue to play a significant role in determining an increased risk for dementia in adulthood.

The Alzheimer's Biomarker Consortium–Down Syndrome (ABC–DS) is a longitudinal study of risk factors for AD in a large cohort of adults with DS. Funded by the NIA and NICHD, the consortium has enrolled approximately 400 individuals with DS, many of whom have been followed for a number of years. A wide range of potential biomarkers of AD is collected as part of the protocol, including blood and CSF-based measures, and cognitive and adaptive functioning measures, as well as MRI and PET scans. Among the current ABC-DS cohort, five individuals who had a prior documented history of acute regression were identified. By matching them with a group of adults with DS who had not had this experience, we have a unique opportunity to examine a larger number of potential biomarker differences. Drawing on potential causes of acute regression and its possible relation to early dementia, it was hypothesized that those individuals with a history of acute regression would have an increased prevalence of risk biomarkers for AD, including greater levels of amyloid deposition, tau and brain neuropathology, and blood-based biomarkers (e.g., neurofilament light chain [NfL]) than a matched group of unaffected adults.
