Amyloid- ß and tau deposition influences cognitive and functional decline in Down syndrome.

This study investigates whether tau has (i) an independent effect from amyloid-ß on changes in cognitive and functional performance and (ii) a synergistic relationship with amyloid-ß in the exacerbation of decline in aging Down syndrome (DS). 105 participants with DS underwent baseline PET [18F]-AV1451 and PET [11C]PiB scans to quantify tau deposition in Braak regions II-VI and the Striatum and amyloid-ß status respectively. Linear Mixed Effects models were implemented to assess how tau and amyloid-ß deposition are related to change over three time points. Tau was a significant independent predictor of cognitive and functional change. The three-way interaction between time, [11C]PiB status and tau was significant in the models of episodic memory and visuospatial cognition. Baseline tau is a significant predictor of cognitive and functional decline, over and above the effect of amyloid-ß status. Results suggest a synergistic relationship between amyloid-ß status and tau as predictors of change in memory and visuospatial cognition.

Support vector machine learning and diffusion-derived structural networks predict amyloid quantity and cognition in adults with Down's syndrome.

Down's syndrome results from trisomy of chromosome 21, a genetic change which also confers a probable 100% risk for the development of Alzheimer's disease neuropathology (amyloid plaque and neurofibrillary tangle formation) in later life. We aimed to assess the effectiveness of diffusion-weighted imaging and connectomic modelling for predicting brain amyloid plaque burden, baseline cognition and longitudinal cognitive change using support vector regression. Ninety-five participants with Down's syndrome successfully completed a full Pittsburgh Compound B (PiB) PET-MR protocol and memory assessment at two timepoints. Our findings indicate that graph theory metrics of node degree and strength based on the structural connectome are effective predictors of global amyloid deposition. We also show that connection density of the structural network at baseline is a promising predictor of current cognitive performance. Directionality of effects were mainly significant reductions in the white matter connectivity in relation to both PiB+ status and greater rate of cognitive decline. Taken together, these results demonstrate the integral role of the white matter during neuropathological progression and the utility of machine learning methodology for non-invasively evaluating Alzheimer's disease prognosis.

Impaired Iron Homeostasis and Haematopoiesis Impacts Inflammation in the Ageing Process in Down Syndrome Dementia.

Down syndrome (DS) subjects are more likely to develop the clinical features of Alzheimer's disease (AD) very early in the disease process due to the additional impact of neuroinflammation and because of activation of innate immunity. Many factors involved in the neuropathology of AD in DS, including epigenetic factors, innate immunity and impaired haematopoiesis, contribute significantly towards the pathophysiology and the enhanced ageing processes seen in DS and as a consequence of the triplication of genes RUNX1, S100ß and OLIG2, together with the influence of proteins that collectively protect from cellular defects and inflammation, which include hepcidin, ferritin, IL-6 and TREM2. This study is aimed at determining whether genetic variants and inflammatory proteins are involved in haematopoiesis and cellular processes in DS compared with age-matched control participants, particularly with respect to neuroinflammation and accelerated ageing. Serum protein levels from DS, AD and control participants were measured by enzyme-linked immunosorbent assay (ELISA). Blood smears and post-mortem brain samples from AD and DS subjects were analysed by immunohistochemistry. RUNX1 mRNA expression was analysed by RT-PCR and in situ hybridisation in mouse tissues. Our results suggest that hepcidin, S100ß and TREM2 play a critical role in survival and proliferation of glial cells through a common shared pathway. Blood smear analysis showed the presence of RUNX1 in megakaryocytes and platelets, implying participation in myeloid cell development. In contrast, hepcidin was expressed in erythrocytes and in platelets, suggesting a means of possible entry into the brain parenchyma via the choroid plexus (CP). The gene product of RUNX1 and hepcidin both play a critical role in haematopoiesis in DS. We propose that soluble TREM2, S100ß and hepcidin can migrate from the periphery via the CP, modulate the blood-brain immune axis in DS and could form an important and hitherto neglected avenue for possible therapeutic interventions to reduce plaque formation.

Establishing diagnostic thresholds for Alzheimer's disease in adults with Down syndrome: the Cambridge Examination for Mental Disorders of Older People with Down's Syndrome and Others with Intellectual Disabilities (CAMDEX-DS).

BACKGROUND: Diagnosis of prodromal Alzheimer's disease and Alzheimer's disease dementia in people with Down syndrome is a major challenge. The Cambridge Examination for Mental Disorders of Older People with Down's Syndrome and Others with Intellectual Disabilities (CAMDEX-DS) has been validated for diagnosing prodromal Alzheimer's disease and Alzheimer's disease dementia, but the diagnostic process lacks guidance. AIMS: To derive CAMDEX-DS informant interview threshold scores to enable accurate diagnosis of prodromal Alzheimer's disease and Alzheimer's disease dementia in adults with Down syndrome. METHOD: Psychiatrists classified participants with Down syndrome into no dementia, prodromal Alzheimer's disease and Alzheimer's disease dementia groups. Receiver operating characteristic analyses assessed the diagnostic accuracy of CAMDEX-DS informant interview-derived scores. Spearman partial correlations investigated associations between CAMDEX-DS scores, regional Aß binding (positron emission tomography) and regional cortical thickness (magnetic resonance imaging). RESULTS: Diagnostic performance of CAMDEX-DS total scores were high for Alzheimer's disease dementia (area under the curve (AUC), 0.998; 95% CI 0.953-0.999) and prodromal Alzheimer's disease (AUC = 0.954; 95% CI 0.887-0.982) when compared with healthy adults with Down syndrome. When compared with those with mental health conditions but no Alzheimer's disease, CAMDEX-DS Section B scores, denoting memory and orientation ability, accurately diagnosed Alzheimer's disease dementia (AUC = 0.958; 95% CI 0.892-0.984), but were unable to diagnose prodromal Alzheimer's disease. CAMDEX-DS total scores exhibited moderate correlations with cortical Aß (r ~ 0.4 to 0.6, P ≤ 0.05) and thickness (r ~ -0.4 to -0.44, P ≤ 0.05) in specific regions. CONCLUSIONS: CAMDEX-DS total score accurately diagnoses Alzheimer's disease dementia and prodromal Alzheimer's disease in healthy adults with Down syndrome.

Measuring cerebral perfusion with [11C]-PiB R1 in Down syndrome: associations with amyloid burden and longitudinal cognitive decline.

Positron emission tomography imaging of glucose hypometabolism and amyloid deposition are two well-established methods to evaluate preclinical changes in Alzheimer's disease and people with Down syndrome. However, the use of both imaging modalities may overburden participants, particularly those with intellectual disabilities and cognitive impairment. The relative tracer delivery of the [11C]-Pittsburgh Compound B has been proposed as a viable surrogate for cerebral perfusion. Here, we studied the impact of amyloid pathology on perfusion changes in Down syndrome and evaluated its associations with cognitive impairment. In total, 47 adults with Down syndrome underwent the [11C]-Pittsburgh Compound B imaging and structural imaging. The structural data were processed with Freesurfer to obtain anatomical segmentations and cortical thickness. The relative tracer delivery from [11C]-Pittsburgh Compound B was derived using a simplified reference tissue model. The sample was stratified into those with minimal amyloid burden (n = 25) and those with elevated amyloid (n = 22). We found significant and widespread reductions of cerebral perfusion in those with elevated amyloid burden, independent of age, gender, cognitive function and cortical thickness. In addition, cerebral perfusion was associated with the cognitive impairment among the Down syndrome group with elevated amyloid burden. These findings highlight the promising utility of the relative tracer delivery of the [11C]-Pittsburgh Compound B as a surrogate index in clinical trials for monitoring disease progression or tracking physiologic changes over time in Down syndrome.