Frontal White Matter Integrity in Adults with Down Syndrome with and without Dementia

Adults with Down syndrome (DS) are at high risk for developing Alzheimer\u27s disease after the age of 40 years. To detect white matter (WM) changes in the brain linked to dementia, fractional anisotropy (FA) from diffusion tensor imaging was used. We hypothesized that adults with DS without dementia (DS n = 10), DS with dementia (DSAD n = 10) and age matched non-DS subjects (CTL n = 10) would show differential levels of FA and an association with scores from the Brief Praxis Test and the Severe Impairment Battery. WM integrity differences in DS compared with CTL were found predominantly in the frontal lobes. Across all DS adults, poorer Brief Praxis Test performance correlated with reduced FA in the corpus callosum as well as several association tracts, primarily within frontoparietal regions. Our results demonstrate significantly lower WM integrity in DS compared with controls, particularly in the frontal tracts. DS-related WM integrity reductions in a number of tracts were associated with poorer cognition. These preliminary results suggest that late myelinating frontal pathways may be vulnerable to aging in DS

Differential effects of Down's syndrome and Alzheimer's neuropathology on default mode connectivity.

Down's syndrome is a chromosomal disorder that invariably results in both intellectual disability and Alzheimer's disease neuropathology. However, only a limited number of studies to date have investigated intrinsic brain network organisation in people with Down's syndrome, none of which addressed the links between functional connectivity and Alzheimer's disease. In this cross-sectional study, we employed 11 C-Pittsburgh Compound-B (PiB) positron emission tomography in order to group participants with Down's syndrome based on the presence of fibrillar beta-amyloid neuropathology. We also acquired resting state functional magnetic resonance imaging data to interrogate the connectivity of the default mode network; a large-scale system with demonstrated links to Alzheimer's disease. The results revealed widespread positive connectivity of the default mode network in people with Down's syndrome (n = 34, ages 30-55, median age = 43.5) and a stark lack of anti-correlation. However, in contrast to typically developing controls (n = 20, ages 30-55, median age = 43.5), the Down's syndrome group also showed significantly weaker connections in localised frontal and posterior brain regions. Notably, while a comparison of the PiB-negative Down's syndrome group (n = 19, ages 30-48, median age = 41.0) to controls suggested that alterations in default mode connectivity to frontal brain regions are related to atypical development, a comparison of the PiB-positive (n = 15, ages 39-55, median age = 48.0) and PiB-negative Down's syndrome groups indicated that aberrant connectivity in posterior cortices is associated with the presence of Alzheimer's disease neuropathology. Such distinct profiles of altered connectivity not only further our understanding of the brain physiology that underlies these two inherently linked conditions but may also potentially provide a biomarker for future studies of neurodegeneration in people with Down's syndrome

Fully-automated μMRI morphometric phenotyping of the Tc1 mouse model of Down Syndrome

We describe a fully automated pipeline for the morphometric phenotyping of mouse brains from μMRI data, and show its application to the Tc1 mouse model of Down syndrome, to identify new morphological phenotypes in the brain of this first transchromosomic animal carrying human chromosome 21. We incorporate an accessible approach for simultaneously scanning multiple ex vivo brains, requiring only a 3D-printed brain holder, and novel image processing steps for their separation and orientation. We employ clinically established multi-atlas techniques-superior to single-atlas methods-together with publicly-available atlas databases for automatic skull-stripping and tissue segmentation, providing high-quality, subject-specific tissue maps. We follow these steps with group-wise registration, structural parcellation and both Voxel- and Tensor-Based Morphometry-advantageous for their ability to highlight morphological differences without the laborious delineation of regions of interest. We show the application of freely available open-source software developed for clinical MRI analysis to mouse brain data: NiftySeg for segmentation and NiftyReg for registration, and discuss atlases and parameters suitable for the preclinical paradigm. We used this pipeline to compare 29 Tc1 brains with 26 wild-type littermate controls, imaged ex vivo at 9.4T. We show an unexpected increase in Tc1 total intracranial volume and, controlling for this, local volume and grey matter density reductions in the Tc1 brain compared to the wild-types, most prominently in the cerebellum, in agreement with human DS and previous histological findings

Investigating brain alterations in the Dp1Tyb mouse model of Down syndrome

Down syndrome (DS) is one of the most common birth defects and the most prevalent genetic form of intellectual disability. DS arises from trisomy of chromosome 21, but its molecular and pathological consequences are not fully understood. In this study, we compared Dp1Tyb mice, a DS model, against their wild-type (WT) littermates of both sexes to investigate the impact of DS-related genetic abnormalities on the brain phenotype. We performed in vivo whole brain magnetic resonance imaging (MRI) and hippocampal 1H magnetic resonance spectroscopy (MRS) on the animals at 3 months of age. Subsequently, ex vivo MRI scans and histological analyses were conducted post-mortem. Our findings unveiled the following neuroanatomical and biochemical alterations in the Dp1Tyb brains: a smaller surface area and a rounder shape compared to WT brains, with DS males also presenting smaller global brain volume compared with the counterpart WT. Regional volumetric analysis revealed significant changes in 26 out of 72 examined brain regions, including the medial prefrontal cortex and dorsal hippocampus. These alterations were consistently observed in both in vivo and ex vivo imaging data. Additionally, high-resolution ex vivo imaging enabled us to investigate cerebellar layers and hippocampal subregions, revealing selective areas of decrease and remodelling in these structures. An analysis of hippocampal metabolites revealed an elevation in glutamine and the glutamine/glutamate ratio in the Dp1Tyb mice compared to controls, suggesting a possible imbalance in the excitation/inhibition ratio. This was accompanied by the decreased levels of taurine. Histological analysis revealed fewer neurons in the hippocampal CA3 and DG layers, along with an increase in astrocytes and microglia. These findings recapitulate multiple neuroanatomical and biochemical features associated with DS, enriching our understanding of the potential connection between chromosome 21 trisomy and the resultant phenotype

Distinct neuroanatomical and neuropsychological features of Down syndrome compared to related neurodevelopmental disorders: a systematic review

ObjectivesWe critically review research findings on the unique changes in brain structure and cognitive function characteristic of Down syndrome (DS) and summarize the similarities and differences with other neurodevelopmental disorders such as Williams syndrome, 22q11.2 deletion syndrome, and fragile X syndrome.MethodsWe conducted a meta-analysis and systematic literature review of 84 studies identified by searching PubMed, Google Scholar, and Web of Science from 1977 to October 2022. This review focuses on the following issues: (1) specific neuroanatomic and histopathological features of DS as revealed by autopsy and modern neuroimaging modalities, (2) language and memory deficits in DS, (3) the relationships between these neuroanatomical and neuropsychological features, and (4) neuroanatomic and neuropsychological differences between DS and related neurodevelopmental syndromes.ResultsNumerous post-mortem and morphometric neuroimaging investigations of individuals with DS have reported complex changes in regional brain volumes, most notably in the hippocampal formation, temporal lobe, frontal lobe, parietal lobe, and cerebellum. Moreover, neuropsychological assessments have revealed deficits in language development, emotional regulation, and memory that reflect these structural changes and are more severe than expected from general cognitive dysfunction. Individuals with DS also show relative preservation of multiple cognitive, linguistic, and social domains compared to normally developed controls and individuals with other neurodevelopmental disorders. However, all these neurodevelopment disorders exhibit substantial heterogeneity among individuals.ConclusionPeople with Down syndrome demonstrate unique neurodevelopmental abnormalities but cannot be regarded as a homogenous group. A comprehensive evaluation of individual intellectual skills is essential for all individuals with neurodevelopment disorders to develop personalized care programs

Basal forebrain atrophy along the Alzheimer's disease continuum in adults with Down syndrome

Background: Basal forebrain (BF) degeneration occurs in Down syndrome (DS)-associated Alzheimer's disease (AD). However, the dynamics of BF atrophy with age and disease progression, its impact on cognition, and its relationship with AD biomarkers have not been studied in DS. Methods: We included 234 adults with DS (150 asymptomatic, 38 prodromal AD, and 46 AD dementia) and 147 euploid controls. BF volumes were extracted from T-weighted magnetic resonance images using a stereotactic atlas in SPM12. We assessed BF volume changes with age and along the clinical AD continuum and their relationship to cognitive performance, cerebrospinal fluid (CSF) and plasma amyloid/tau/neurodegeneration biomarkers, and hippocampal volume. Results: In DS, BF volumes decreased with age and along the clinical AD continuum and significantly correlated with amyloid, tau, and neurofilament light chain changes in CSF and plasma, hippocampal volume, and cognitive performance. Discussion: BF atrophy is a potentially valuable neuroimaging biomarker of AD-related cholinergic neurodegeneration in DS

Altered spontaneous brain activity in Down Syndrome and its relation with cognitive outcome

Although Down syndrome (DS) is the most common genetic cause of neurodevelopmental delay, few neuroimaging studies have explored this population. This investigation aimed to study whole-brain resting-state spontaneous brain activity using fractional amplitude of low-frequency fluctuation (fALFF) and regional homogeneity (ReHo) strategies to find differences in spontaneous brain activity among young people with DS and controls and to correlate these results with cognitive outcomes. The sample comprised 18 persons with DS (age mean = 28.67, standard deviation = 4.18) and 18 controls (age mean = 28.56, standard deviation = 4.26). fALFF and ReHo analyses were performed, and the results were correlated with other cognitive variables also collected (KBIT-2 and verbal fluency test). Increased activity was found in DS using fALFF in areas involving the frontal and temporal lobes and left cerebellum anterior lobe. Decreased activity in DS was found in the left parietal and occipital lobe, the left limbic lobe and the left cerebellum posterior lobe. ReHo analysis showed increased activity in certain DS areas of the left frontal lobe and left rectus, as well as the inferior temporal lobe. The areas with decreased activity in the DS participants were regions of the frontal lobe and the right limbic lobe. Altered fALFF and ReHo were found in the DS population, and this alteration could predict the cognitive abilities of the participants. To our knowledge, this is the first study to explore regional spontaneous brain activity in a population with DS. Moreover, this study suggests the possibility of using fALFF and ReHo as biomarkers of cognitive function, which is highly important given the difficulties in cognitively evaluating this population to assess dementia. More research is needed, however, to demonstrate its utility

The Down syndrome brain in the presence and absence of fibrillar β-amyloidosis

People with Down syndrome (DS) have a neurodevelopmentally distinct brain and invariably developed amyloid neuropathology by age 50. This cross-sectional study aimed to provide a detailed account of DS brain morphology and the changes occuring with amyloid neuropathology. Forty-six adults with DS underwent structural and amyloid imaging-the latter using Pittsburgh compound B (PIB) to stratify the cohort into PIB-positive (n = 19) and PIB-negative (n = 27). Age-matched controls (n = 30) underwent structural imaging. Group differences in deep gray matter volumetry and cortical thickness were studied. PIB-negative people with DS have neurodevelopmentally atypical brain, characterized by disproportionately thicker frontal and occipitoparietal cortex and thinner motor cortex and temporal pole with larger putamina and smaller hippocampi than controls. In the presence of amyloid neuropathology, the DS brains demonstrated a strikingly similar pattern of posterior dominant cortical thinning and subcortical atrophy in the hippocampus, thalamus, and striatum, to that observed in non-DS Alzheimer's disease. Care must be taken to avoid underestimating amyloid-associated morphologic changes in DS due to disproportionate size of some subcortical structures and thickness of the cortex.This work was supported by the Medical Research Council (grant number: 98480 ). Additional support was received from the NIHR Cambridge Biomedical Research Centre, the NIHR Collaborations in Leadership for Applied Health Research and Care (CLAHRC) for the East of England, the NIHR Cambridge Dementia Biomedical Research Unit, the Down Syndrome Association and the Health Foundation

The importance of understanding individual differences in Down syndrome

In this article, we first present a summary of the general assumptions about Down syndrome (DS) still to be found in the literature. We go on to show how new research has modified these assumptions, pointing to a wide range of individual differences at every level of description. We argue that, in the context of significant increases in DS life expectancy, a focus on individual differences in trisomy 21 at all levels—genetic, cellular, neural, cognitive, behavioral, and environmental—constitutes one of the best approaches for understanding genotype/phenotype relations in DS and for exploring risk and protective factors for Alzheimer’s disease in this high-risk population