Plasma tau phosphorylated at threonine 181 (p-tau181) predicts Alzheimer's disease (AD) pathology with high accuracy in the general population. In this study, we investigated plasma p-tau181 as a ...biomarker of AD in individuals with Down syndrome (DS). We included 366 adults with DS (240 asymptomatic, 43 prodromal AD, 83 AD dementia) and 44 euploid cognitively normal controls. We measured plasma p-tau181 with a Single molecule array (Simoa) assay. We examined the diagnostic performance of p-tau181 for the detection of AD and the relationship with other fluid and imaging biomarkers. Plasma p-tau181 concentration showed an area under the curve of 0.80 95% CI 0.73-0.87 and 0.92 95% CI 0.89-0.95 for the discrimination between asymptomatic individuals versus those in the prodromal and dementia groups, respectively. Plasma p-tau181 correlated with atrophy and hypometabolism in temporoparietal regions. Our findings indicate that plasma p-tau181 concentration can be useful to detect AD in DS.
The risk of severe outcomes following respiratory tract infections is significantly increased in individuals over 60 years, especially in those with chronic medical conditions, i.e., hypertension, ...diabetes, cardiovascular disease, dementia, chronic respiratory disease, and cancer. Down Syndrome (DS), the most prevalent intellectual disability, is caused by trisomy-21 in ~1:750 live births worldwide. Over the past few decades, a substantial body of evidence has accumulated, pointing at the occurrence of alterations, impairments, and subsequently dysfunction of the various components of the immune system in individuals with DS. This associates with increased vulnerability to respiratory tract infections in this population, such as the influenza virus, respiratory syncytial virus, SARS-CoV-2 (COVID-19), and bacterial pneumonias. To emphasize this link, here we comprehensively review the immunobiology of DS and its contribution to higher susceptibility to severe illness and mortality from respiratory tract infections.
In Alzheimer's disease and Down syndrome, cholinergic neurons of the basal forebrain progressively degenerate. This neurotransmitter system is the main source of acetylcholine to the cortex and ...hippocampus. In the mature and fully differentiated central nervous system, the phenotype of forebrain cholinergic neurons and their nerve terminals in cortex and hippocampus depend on the continuous endogenous supply of nerve growth factor (NGF). It has been recently demonstrated that NGF is secreted from cortical neurons in an activity-dependent manner as a precursor molecule, proNGF. Individuals with Alzheimer's disease and Down syndrome exhibit proNGF accumulation in cortex, yet cholinergic neurons become atrophic in both diseases, despite the apparent abundance of the NGF precursor. This review illustrates the recent evidence that NGF metabolism is affected both in Alzheimer's disease and in Down syndrome brains and also discusses a role for amyloid-β peptides and central nervous system inflammation in unleashing such deficits. It further considers the potential of the NGF metabolic pathway as a new pharmacological target to slow down the neurodegenerative process both in Alzheimer's disease and in individuals with Down syndrome.
ObjectivesTo investigate public perspectives on brain health.DesignCross-sectional multilanguage online survey.SettingLifebrain posted the survey on its website and social media and shared it with ...stakeholders. The survey was open from 4 June 2019 to 31 August 2020.Participantsn=27 590 aged ≥18 years from 81 countries in five continents completed the survey. The respondents were predominantly women (71%), middle aged (41–60 years; 37%) or above (>60 years; 46%), highly educated (69%) and resided in Europe (98%).Main outcome measuresRespondents’ views were assessed regarding factors that may influence brain health, life periods considered important to look after the brain and diseases and disorders associated with the brain. We run exploratory linear models at a 99% level of significance to assess correlates of the outcome variables, adjusting for likely confounders in a targeted fashion.ResultsOf all significant effects, the respondents recognised the impact of lifestyle factors on brain health but had relatively less awareness of the role socioeconomic factors might play. Most respondents rated all life periods as important for the brain (95%–96%), although the prenatal period was ranked significantly lower (84%). Equally, women and highly educated respondents more often rated factors and life periods to be important for brain health. Ninety-nine per cent of respondents associated Alzheimer’s disease and dementia with the brain. The respondents made a connection between mental health and the brain, and mental disorders such as schizophrenia and depression were significantly more often considered to be associated with the brain than neurological disorders such as stroke and Parkinson’s disease. Few respondents (<32%) associated cancer, hypertension, diabetes and arthritis with the brain.ConclusionsDifferences in perceptions of brain health were noted among specific segments of the population. Policies providing information about brain-friendly health behaviours and targeting people less likely to have relevant experience may be needed.
Adults with Down syndrome are at an ultra-high risk of developing early-onset Alzheimer's disease. Episodic memory deficits are one of the earliest signs of the disease, but their association with ...regional brain atrophy in the population with Down syndrome has not been explored. We aimed to investigate the neuroanatomical correlates of episodic memory in adults with Down syndrome and symptomatic Alzheimer's disease.
Single-center, cross-sectional study. A total of 139 adults with Down syndrome (85 asymptomatic and 54 with symptomatic Alzheimer's disease) were included in the study (mean age 43.6 ± 10.9 years, 46% female). Episodic memory was assessed using the modified Cued Recall Test. Immediate (trial 1 free immediate recall, trial 3 free immediate recall, total free immediate recall score, and total immediate score) and delayed scores (free delayed recall score and total delayed score) were examined. Cortical thickness from magnetic resonance imaging was determined with surface-based morphometry using the FreeSurfer 6.0 software package. The clusters of reduced cortical thickness were compared between symptomatic and asymptomatic participants to create a cortical atrophy map. Then, the correlation between cortical thickness and the modified Cued Recall Test subscores were separately assessed in symptomatic and asymptomatic subjects, controlling for age, sex, and severity of intellectual disability.
Compared with asymptomatic participants, those with symptomatic Alzheimer's disease showed a pattern of cortical atrophy in posterior parieto-temporo-occipital cortices. In symptomatic subjects, trial 1 immediate free recall significantly correlated with cortical atrophy in lateral prefrontal regions. Trial 3 free immediate recall and total free immediate recall were associated with the most widespread cortical atrophy. Total immediate score was related to posterior cortical atrophy, including lateral parietal and temporal cortex, posterior cingulate cortex, precuneus, and medial temporal lobe areas. Delayed memory scores were associated with cortical atrophy in temporoparietal and medial temporal lobe regions. No significant relationships were observed between episodic memory measures and cortical atrophy in asymptomatic subjects.
Different episodic memory measures were associated with cortical atrophy in specific brain regions in adults with Down syndrome and Alzheimer's disease. These results overlap with those described in sporadic Alzheimer's disease and further support the similarities between Down syndrome-associated Alzheimer's disease and that in the general population.
Background
Down syndrome (DS) is a genetic form of Alzheimer's disease (AD). However, clinical diagnosis is difficult, and experts emphasize the need for detecting intra‐individual cognitive decline.
...Objective
To compare the performance of baseline and longitudinal neuropsychological assessments for the diagnosis of symptomatic AD in DS.
Methods
Longitudinal cohort study of adults with DS. Individuals were classified as asymptomatic, prodromal AD, or AD dementia. We performed receiver operating characteristic curve analyses to compare baseline and longitudinal changes of CAMCOG‐DS and mCRT.
Results
We included 562 adults with DS. Baseline assessments showed good to excellent diagnostic performance for AD dementia (AUCs between 0.82 and 0.99) and prodromal AD, higher than the 1‐year intra‐individual cognitive decline (area under the ROC curve between 0.59 and 0.79 for AD dementia, lower for prodromal AD). Longer follow‐ups increased the diagnostic performance of the intra‐individual cognitive decline.
Discussion
Baseline cognitive assessment outperforms the 1‐year intra‐individual cognitive decline in adults with DS.
We report the neuropathological examination of a patient with Alzheimer's disease (AD) treated for 38 months with low doses of the BACE‐1 inhibitor verubecestat. Brain examination showed small plaque ...size, reduced dystrophic neurites around plaques and reduced synaptic‐associated Aβ compared with a group of age‐matched untreated sporadic AD (SAD) cases. Our findings suggest that BACE‐1 inhibition has an impact on synaptic soluble Aβ accumulation and neuritic derangement in AD.
AF710B (aka ANAVEX 3-71) is a novel selective allosteric M1 muscarinic and sigma-1 receptor agonist. In 3×Tg-AD mice, AF710B attenuates cognitive deficits and decreases Alzheimer-like hallmarks. We ...now report on the long-lasting disease-modifying properties of AF710B in McGill-R-Thy1-APP transgenic (Tg) rats.
Chronic treatment with AF710B (10 μg/kg) was initiated in postplaque 13-month-old Tg rats. Drug or vehicle was administered orally daily for 4.5 months and interrupted 5 weeks before behavioral testing.
AF710B long-term treatment reverted the cognitive deficits associated with advanced Alzheimer-like amyloid neuropathology in Tg rats. These effects were accompanied by reductions in amyloid pathology and markers of neuroinflammation and increases in amyloid cerebrospinal fluid clearance and levels of a synaptic marker. Importantly, these effects were maintained following a 5-week interruption of the treatment.
With M1/sigma-1 activity and long-lasting disease-modifying properties at low dose, AF710B is a promising novel therapeutic agent for treating Alzheimer's disease.
•AF710B is a concomitant allosteric M1 receptor agonist and sigma-1 receptor agonist.•In McGill transgenic rats, AF710B shows long-lasting disease-modifying properties.•AF710B had procognitive effects in McGill rats and raises levels of a synaptic marker.•AF710B reduced brain amyloid burden and increased Aβ levels in cerebrospinal fluid.
Background
Down syndrome (DS) is a genetically determined form of Alzheimer’s disease (AD), and a priority population to study early AD changes. This study explores inflammatory markers in biofluids ...over the course of the AD continuum in adults with DS.
Method
This is a cross‐sectional study of the Olink Target 96 Inflammation (v.3022) panel in paired plasma and CSF from adults with DS from the DABNI cohort across the AD continuum (83 asymptomatic and 109 symptomatic), 60 cognitively unimpaired controls and 130 sporadic AD (sAD) patients. See Table for demographics. We used linear regression to compare group differences, including age and sex as covariates. Age was excluded and intellectual disability was added as a covariate when comparing across AD stages in DS. We controlled the false discovery rate using the Bonferonni‐Hochberg method and considered only statistically and biologically relevant changes (fold‐change+/‐10%, adj.p<0.05).
Result
We detected 59/96 inflammatory markers on the panel in CSF and 81/96 in plasma. In asymptomatic DS vs CN, 12 inflammatory markers were decreased (<0.84‐fold, adj.p<0.02) and 3 were increased (>1.27‐fold, adj.p<0.03) in CSF. In the same comparison in plasma, 2 were decreased (<0.84‐fold, adj.p<0.03) and 26 were increased (>1.13‐fold, adj.p<0.04). Over the AD continuum in DS, 29 inflammatory markers were increased (>1.1‐fold, adj.p<0.04) and 1 was decreased (0.78‐fold, adj.p = 0.003) in CSF. We did not see the same profile in sAD vs CN CSF (1 marker; 1.59‐fold, adj.p<0.0001). To focus on CNS inflammation, we restricted plasma analyses to the 11 inflammatory markers that showed AD‐associated changes in CSF and correlated between both biofluids (r2 = 0.03‐0.43; p<0.04). CCL23, CCL3, CXCL9 and CXCL10 were increased over AD stages in plasma (>1.15‐fold, adj.p<0.03) with similar effect sizes to those in CSF (>1.17‐fold, adj.p<0.02). We observed no change in those inflammatory markers in sAD vs CN plasma (all adj.p>0.14).
Conclusion
Trisomy 21 is associated with a distinct inflammatory profile in CSF and plasma. However, certain markers showed similar changes in both biofluids across the AD continuum in DS. CCL23, CCL3, CXCL9 and CXCL10 represent promising novel plasma biomarkers of AD‐related inflammation in DS.
Table. Demographics (%/mean+sd) for the participants used in this study.
PDF
