Search

Introduction: The Down syndrome population has a high prevalence for dementia, often showing their first clinical symptoms in their 40s. Methods: In a longitudinal cohort, we investigate whether amyloid deposition at time point 1 (TP1) could predict cortical thickness change at time point 2 (TP2). The association between tau burden and cortical thickness was also examined at time point 3 (TP3). Results: Between TP1 and TP2 there was pronounced cortical thinning in temporo‐parietal cortices and cortical thickening in the frontal cortex. Baseline amyloid burden was strongly associated to cortical thinning progression, especially in the temporo‐parietal regions. At TP3, tau deposition negatively correlated with cortical atrophy in regions where tau usually accumulates at later Braak stages. Discussion: A higher amount of amyloid accumulation triggers a cascade of changes of disease‐causing processes that eventually lead to dementia. As expected, we found that regions where tau usually accumulates were those also displaying high levels of cortical atrophy. [ABSTRACT FROM AUTHOR]

Background: Synaptic loss is a prominent and early feature of many neurodegenerative diseases. Objectives: We tested the hypothesis that synaptic density is reduced in the primary tauopathies of progressive supranuclear palsy (PSP) (Richardson's syndrome) and amyloid‐negative corticobasal syndrome (CBS). Methods: Forty‐four participants (15 CBS, 14 PSP, and 15 age‐/sex‐/education‐matched controls) underwent PET with the radioligand [11C]UCB‐J, which binds to synaptic vesicle glycoprotein 2A, a marker of synaptic density; participants also had 3 Tesla MRI and clinical and neuropsychological assessment. Results: Nine CBS patients had negative amyloid biomarkers determined by [11C]PiB PET and hence were deemed likely to have corticobasal degeneration (CBD). Patients with PSP‐Richardson's syndrome and amyloid‐negative CBS were impaired in executive, memory, and visuospatial tasks. [11C]UCB‐J binding was reduced across frontal, temporal, parietal, and occipital lobes, cingulate, hippocampus, insula, amygdala, and subcortical structures in both PSP and CBD patients compared to controls (P < 0.01), with median reductions up to 50%, consistent with postmortem data. Reductions of 20% to 30% were widespread even in areas of the brain with minimal atrophy. There was a negative correlation between global [11C]UCB‐J binding and the PSP and CBD rating scales (R = –0.61, P < 0.002; R = –0.72, P < 0.001, respectively) and a positive correlation with the revised Addenbrooke's Cognitive Examination (R = 0.52; P = 0.01). Conclusions: We confirm severe synaptic loss in PSP and CBD in proportion to disease severity, providing critical insight into the pathophysiology of primary degenerative tauopathies. [11C]UCB‐J may facilitate treatment strategies for disease‐modification, synaptic maintenance, or restoration. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Background: Amyloid‐β accumulation in the brain has been associated with decline in cognitive functioning in adults with Down Syndrome (DS). Despite the significant relationship between in vivo Amyloid‐β and tau pathology, no studies have assessed whether tau potentiates the relationship between amyloid‐β and cognitive decline in DS. Here we investigate whether (i) tau has an independent effect on changes in cognition; (ii) tau has a synergistic relationship with amyloid in the exacerbation of cognitive decline. Method: A baseline cohort of 105 participants with DS underwent PET AV‐1451 and PiB scans to quantify tau and Amyloid‐β deposition. Neuropsychological assessment of participants included a test for episodic memory (Cued Recall), visuospatial ability (WISC‐IV Block Design and Haxby Extension) and global cognition (DSMSE). Cognition was re‐assessed at 16 (n = 105) and 32 months (n=26) after baseline. Amyloid‐β burden was quantified categorically as PiB+/‐ where PiB+ status was defined as PiB standard uptake value ratio (SUVR) above a defined threshold. Braak regions (2‐6) and the Striatum were used for generating the SUVR for AV‐1451. Linear Mixed Effects models were implemented to assess the independent effects of tau and PiB status on change in cognition. Additional models tested the 3‐way interactions between tau, PiB status and time for each ROI. P‐values were adjusted via the FDR method. Result: For the memory outcome, the interactions between time and tau (with PiB status – time interactions also included in the model) were significant for all ROIs, except the Striatum, while Braak regions 3 to 5 were significantly associated with change in DSMSE scores. All ROIs' tau showed a significant interaction with time for the Block Design task. The three‐way interaction between time, PiB status and striatal tau was significant in the models of memory change. Braak 5 and tau showed a significant interaction with time and PiB status for the visuospatial ability outcome (Fig 1‐4). Conclusion: There was evidence for a significant independent effect of baseline tau on cognitive change, over and above the effect of amyloid status. We also found evidence for a synergistic relationship between PiB status and tau as predictors of change in memory and visuospatial ability. [ABSTRACT FROM AUTHOR]

Background: Down Syndrome (DS) is the most common neurodevelopmental disorder caused by the presence of trisomy 21 (1:800 to 1:1000 live births worldwide). The extra copy of chromosome 21 is associated with a 4‐5 fold overexpression of the amyloid precursor protein (APP) gene, increased accumulation of cerebral beta‐amyloid (Aβ) in the brain, subsequent neurofibrillary tangle (NFT) formation and neurodegeneration. This study investigates whether tau has (i) an independent effect from amyloid on changes in cognitive and functional performance and (ii) a synergistic relationship with amyloid in the exacerbation of decline in aging DS. Method: 105 participants with DS underwent baseline PET AV‐1451 and PET PiB scans to quantify tau deposition in Braak regions II‐VI and Striatum and amyloid‐β status respectively. A longitudinal cognitive testing battery was performed consistent with previous research in the same study cohort, with all participants completing at least two timepoints, and 26 completing three timepoints, with an average of 17 months between study visits. Linear Mixed Effects models were implemented to assess how tau and amyloid deposition are related to change over three time points. Result: Three cognitive outcome measures showed a significant effect of time: the Free + Cued Recall (t = ‐6.09, p < 0.01), Cued Intrusions (t = 3.19, p < 0.01) and NTG (z = 5.33, p = 0) variables. Tau SUVR was a significant independent predictor of cognitive and functional change. The three‐way interaction between time, PiB status and tau was significant in the models of episodic memory and visuospatial cognition (Figures 1‐3). Conclusion: Our results contribute to an emerging framework in which the elevated risk of developing dementia involves mechanisms associated with both amyloid‐β and tau aggregation. This is supported by our finding that when including the two‐way interactions between amyloid status and time and regional tau and time in the same model, tau seems to be a more significant predictor of cognitive change over time than amyloid status. Our results suggest a synergistic relationship between PiB status and tau as predictors of change in memory and visuospatial cognition. [ABSTRACT FROM AUTHOR]

Neuroinflammation occurs in frontotemporal dementia, however its timing relative to protein aggregation and neuronal loss is unknown. Using positron emission tomography and magnetic resonance imaging to quantify these processes in a pre‐symptomatic carrier of the 10 + 16 MAPT mutation, we show microglial activation in frontotemporal regions, despite a lack of protein aggregation or atrophy in these areas. The distribution of microglial activation better discriminated the carrier from controls than did protein aggregation at this pre‐symptomatic disease stage. Our findings suggest an early role for microglial activation in frontotemporal dementia. Longitudinal studies are needed to explore the causality of this pathophysiological association. [ABSTRACT FROM AUTHOR]

The PET ligand [18F]AV‐1451 was developed to bind tau pathology in Alzheimer's disease, but increased binding has been shown in both genetic tauopathies and in semantic dementia, a disease strongly associated with TDP‐43 pathology. Here we assessed [18F]AV‐1451 binding in behavioral variant frontotemporal dementia due to a hexanucleotide repeat expansion in C9orf72, characterized by TDP‐43 pathology. We show that the C9orf72 mutation increases binding in frontotemporal cortex, with a distinctive distribution of binding compared with healthy controls. [ABSTRACT FROM AUTHOR]

The validation of tau radioligands could improve the diagnosis of frontotemporal lobar degeneration and the assessment of disease-modifying therapies. Here, we demonstrate that binding of the tau radioligand [18F] AV-1451 was significantly abnormal in both magnitude and distribution in a patient with familial frontotemporal dementia due to a MAPT 10 + 16C>T gene mutation, recapitulating the pattern of neuropathology seen in her father. Given the genetic diagnosis and the non-Alzheimer's pathology, these findings suggest that [18F] AV-1451 might be a useful biomarker in primary tauopathies. Largerscale in vivo and post-mortem studies will be needed to assess the technique's specificity. [ABSTRACT FROM AUTHOR]

Introduction Adults with Down syndrome (DS) invariably develop Alzheimer's disease (AD) neuropathology. Understanding amyloid deposition in DS can yield crucial information about disease pathogenesis. Methods Forty-nine adults with DS aged 25–65 underwent positron emission tomography with Pittsburgh compound–B (PIB). Regional PIB binding was assessed with respect to age, clinical, and cognitive status. Results Abnormal PIB binding became evident from 39 years, first in striatum followed by rostral prefrontal-cingulo-parietal regions, then caudal frontal, rostral temporal, primary sensorimotor and occipital, and finally parahippocampal cortex, thalamus, and amygdala. PIB binding was related to age, diagnostic status, and cognitive function. Discussion PIB binding in DS, first appearing in striatum, began around age 40 and was strongly associated with dementia and cognitive decline. The absence of a substantial time lag between amyloid accumulation and cognitive decline contrasts to sporadic/familial AD and suggests this population's suitability for an amyloid primary prevention trial. [ABSTRACT FROM AUTHOR]

Background: Alzheimer's Disease (AD) is known to pathologically develop in Downs Syndrome in almost one hundred percent of cases, although at present structural changes to the brain are minimally utilized for diagnoses of neurodegeneration due to limited understanding of which white matter alterations are directly relevant to clinical presentation. By novel application of machine learning to metrics of the structural connectome in Downs Syndrome, this project aims to identify specific white matter networks that significantly impact classification of cases into AD positive or negative. Method: A pilot sample of 21 healthy Down's syndrome participants and 4 Down's syndrome participants with a diagnostic consensus of either mild cognitive impairment (MCI) or dementia underwent diffusion‐weighted and T1‐weighted MRI scanning at 3T. These data form part of a consortium, which will be utilised to increase sample size for future iterations of this analysis. Whole brain structural connectomes were produced for each participant, utilizing fibre orientation distributions and spherical deconvolution informed filtering of the tractograms. For accurate localisation of nodes to brain regions, the T1‐weighted scan was pre‐processed, segmented, parcellated and co‐registered to diffusion space. Networks were created by examining connection density between T1‐delineated structural nodes. Connection density matrices were used to train and test a support vector machine (SVM) classifier. Results: Preliminary results show widespread reduction in network structural connectivity in the Down's syndrome participants diagnosed with dementia or mild cognitive impairment (Fig. 1). The parietal, occipital and to a lesser extent the temporal areas of the network exhibit the most marked decreases in connection density, and no edges of the network displayed increased connection density in dementia or MCI patients compared to healthy Downs syndrome. Multivariate analyses indicate that although SVM classification of the networks has a >80% accuracy, false‐negative classifications were common due to the low number of Down's syndrome dementia participants. Conclusions: This pilot application of SVM to diffusion‐derived brain networks in Down's syndrome demonstrates utility and feasibility as a diagnostic classifier. We expect that increased sample size should yield a more robust trained model. [ABSTRACT FROM AUTHOR]