Characterization of neurodegenerative pathologies in adult and pediatric subjects with Down syndrome

Abstract

BackgroundDown syndrome (DS) is frequently associated with Alzheimer's disease neuropathologic change (ADNC). However, studies assessing the full spectrum of neurodegenerative pathologies using modern consensus and staging criteria remain limited.ObjectiveWe aimed to elucidate the progression of neurodegenerative pathologies in DS and to explore the prevalence of comorbid pathologies across a broad age range (0-76 years), using comprehensive neuropathological assessments.MethodsWe conducted a two-phase analysis. First, we investigated an institutional dataset, followed by a pooled analysis incorporating data from the National Alzheimer's Coordinating Center and four published studies. Pathologies assessed included amyloid-β (Aβ), tau, α-synuclein, TDP-43, cerebral amyloid angiopathy (CAA), other cerebrovascular diseases (CVD), hippocampal sclerosis (HS), and basal ganglia mineralizations (BGM).ResultsDiffuse Aβ plaques appeared by age 11, with neuritic plaques emerging in the mid-thirties. Mild tau pathology, including pre-tangles and neuropil threads, first emerged in the second decade, with neurofibrillary tangles fully present in the fourth decade, always concurrent with Aβ plaques. All individuals over 30 exhibited ADNC. α-Synuclein pathology was observed in 27% of cases, while aging-related tau astrogliopathy (ARTAG), HS, and limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC) were rare. CVD was present in approximately 60%, CAA was nearly universal (98%) after age 50, and 18% had BGM. Brain weight was consistently below the 25th percentile, even in younger individuals without ADNC.ConclusionsDS shows a distinct neurodegenerative trajectory with early Aβ deposition. CAA, arteriolosclerosis, BGM, and α-synuclein pathology were highly prevalent, while ARTAG and LATE-NC were infrequently observed.

Keywords: Alzheimer's disease; Down syndrome; TDP-43; aging-related tau astrogliopathy; alpha-synuclein; amyloid-β; basal ganglia mineralization; hippocampal sclerosis; neurofibrillary tangles; tau.

Figure 1.

Neuropathological changes in DS. (A) In case #6, aged 11 years, amyloid deposits are present in the frontal cortex in the absence of any tau pathology. (B) The area marked in A is shown at a higher magnification. (C) In case #7, aged 14 years, the hippocampus is mostly devoid of tau pathology. (D) At a higher magnification, the area marked in C is shown to exhibit very mild tau pathology in the form of a few pretangles and neuropil threads. This case did not exhibit any amyloid deposits. (E) In case #28, aged 56 years, Thal phase 5 (A score of 3) is evident, characterized by numerous amyloid deposits in the cerebellar cortex. (F) In the same case, Braak stage VI (B score of 3) is evident, showing abundant tau accumulation with tangles and neuropil threads in the primary visual cortex. (G) In case #34, aged 70 years, a section of the cerebellum reveals multiple vessels with intramural amyloid-β accumulation, indicating cerebral amyloid angiopathy (CAA). (H) The amygdala of case #33, aged 70 years, exhibits notable α-synuclein accumulation. This case also had α-synuclein-positive Lewy bodies in bilateral olfactory tracts/bulbs (not shown).

Figure 2.

Average ABC scores and ADNC level by age decade in UTSW cohort (n = 34). ADNC level: 0-none, 1-low, 2-intermediate, 3-high (subjects in first decade of life not shown due to lack of pathological findings).

Figure 3.

Scatterplot: age at death versus ABC scores and ADNC level in UTSW cohort (N = 34).

Figure 4.

Scatterplot: age at death versus ABC scores and ADNC level in ADNC+ subjects in UTSW cohort (n = 26).

Figure 5.

Scatterplot: age at death versus brain weight in UTSW cohort (N = 34).

Figure 6.

Mineralizations in the basal ganglia. (A) Low magnification view depicting mineralizations in the basal ganglia, particularly in the globus pallidus of case #30, aged 59 years. (B) High magnification view of A showing a focus with striking mineralizations. (C) The mineralizations in the same case (#30) are positive for ferric iron. (D) In case #31, aged 61 years, the mineralizations also exhibit positivity for calcium.

Figure 7.

Average ABC scores and ADNC level by age decade in the combined dataset. ADNC level: 0-none, 1-low, 2-intermediate, 3-high (subjects in first decade of life not shown due to lack of pathological findings).