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Contains fulltext : 248802.pdf (Publisher’s version ) (Closed access)

Background:Cerebral amyloid angiopathy (CAA) is one of the major causes of intracerebral hemorrhage and vascular dementia in older adults. Early diagnosis will provide clinicians with an opportunity to intervene early with suitable strategies, highlighting the importance of pre-symptomatic CAA biomarkers. Objective:Investigation of pre-symptomatic CAA related blood metabolite alterations in Dutch-type hereditary CAA mutation carriers (D-CAA MCs). Methods:Plasma metabolites were measured using mass-spectrometry (AbsoluteIDQ® p400 HR kit) and were compared between pre-symptomatic D-CAA MCs (n = 9) and non-carriers (D-CAA NCs, n = 8) from the same pedigree. Metabolites that survived correction for multiple comparisons were further compared between D-CAA MCs and additional control groups (cognitively unimpaired adults). Results:275 metabolites were measured in the plasma, 22 of which were observed to be significantly lower in theD-CAAMCs compared to D-CAA NCs, following adjustment for potential confounding factors age, sex, and APOE ε4 (p < 0.05). After adjusting for multiple comparisons, only spermidine remained significantly lower in theD-CAAMCscompared to theD-CAA NCs (p < 0.00018). Plasma spermidine was also significantly lower in D-CAA MCs compared to the cognitively unimpaired young adult and older adult groups (p < 0.01). Spermidinewas also observed to correlate with CSF Aβ40 (rs = 0.621, p = 0.024), CSF Aβ42 (rs = 0.714, p = 0.006), and brain Aβ load (rs = –0.527, p = 0.030). Conclusion:The current study provides pilot data on D-CAA linked metabolite signals, that also associated with Aβ neuropathology and are involved in several biological pathways that have previously been linked to neurodegeneration and dementia.

Development of tau-based therapies for Alzheimer’s disease requires an understanding of the timing of disease-related changes in tau. We quantified the phosphorylation state at multiple sites of the tau protein in cerebrospinal fluid markers across four decades of disease progression in dominantly inherited Alzheimer’s disease. We identified a pattern of tau staging where site-specific phosphorylation changes occur at different periods of disease progression and follow distinct trajectories over time. These tau phosphorylation state changes are uniquely associated with structural, metabolic, neurodegenerative and clinical markers of disease, and some (p-tau217 and p-tau181) begin with the initial increases in aggregate amyloid-β as early as two decades before the development of aggregated tau pathology. Others (p-tau205 and t-tau) increase with atrophy and hypometabolism closer to symptom onset. These findings provide insights into the pathways linking tau, amyloid-β and neurodegeneration, and may facilitate clinical trials of tau-based treatments.

Neurofilament light chain (NfL) is a promising fluid biomarker of disease progression for various cerebral proteopathies. Here we leverage the unique characteristics of the Dominantly Inherited Alzheimer Network and ultrasensitive immunoassay technology to demonstrate that NfL levels in the cerebrospinal fluid (n = 187) and serum (n = 405) are correlated with one another and are elevated at the presymptomatic stages of familial Alzheimer’s disease. Longitudinal, within-person analysis of serum NfL dynamics (n = 196) confirmed this elevation and further revealed that the rate of change of serum NfL could discriminate mutation carriers from non-mutation carriers almost a decade earlier than cross-sectional absolute NfL levels (that is, 16.2 versus 6.8 years before the estimated symptom onset). Serum NfL rate of change peaked in participants converting from the presymptomatic to the symptomatic stage and was associated with cortical thinning assessed by magnetic resonance imaging, but less so with amyloid-β deposition or glucose metabolism (assessed by positron emission tomography). Serum NfL was predictive for both the rate of cortical thinning and cognitive changes assessed by the Mini–Mental State Examination and Logical Memory test. Thus, NfL dynamics in serum predict disease progression and brain neurodegeneration at the early presymptomatic stages of familial Alzheimer’s disease, which supports its potential utility as a clinically useful biomarker.

Objective To determine whether amyloid imaging with the positron emission tomography (PET) agent Pittsburgh compound B (PiB) can detect vascular β‐amyloid (Aβ) in the essentially pure form of cerebral amyloid angiopathy associated with the Dutch‐type hereditary cerebral amyloid angiopathy (D‐CAA) mutation. Methods PiB retention in a cortical composite of frontal, lateral, and retrosplenial regions (FLR) was measured by PiB‐PET in 19 D‐CAA mutation carriers (M+; 13 without neurologic symptoms, 6 with prior lobar intracerebral hemorrhage) and 17 mutation noncarriers (M−). Progression of PiB retention was analyzed in a subset of 18 serially imaged individuals (10 asymptomatic M+, 8 M−). We also analyzed associations between PiB retention and cerebrospinal fluid (CSF) Aβ concentrations in 17 M+ and 11 M− participants who underwent lumbar puncture and compared the findings to PiB‐PET and CSF Aβ in 37 autosomal dominant Alzheimer disease (ADAD) mutation carriers. Results D‐CAA M+ showed greater age‐dependent FLR PiB retention (p < 0.001) than M−, and serially imaged asymptomatic M+ demonstrated greater longitudinal increases (p = 0.004). Among M+, greater FLR PiB retention associated with reduced CSF concentrations of Aβ40 (r = −0.55, p = 0.021) but not Aβ42 (r = 0.01, p = 0.991). Despite comparably low CSF Aβ40 and Aβ42, PiB retention was substantially less in D‐CAA than ADAD (p < 0.001). Interpretation Increased PiB retention in D‐CAA and correlation with reduced CSF Aβ40 suggest this compound labels vascular amyloid, although to a lesser degree than amyloid deposits in ADAD. Progression in PiB signal over time suggests amyloid PET as a potential biomarker in trials of candidate agents for this untreatable cause of hemorrhagic stroke. ANN NEUROL 2019;86:616–625

Introduction Little is known about effects of physical activity (PA) in genetically driven early‐onset autosomal dominant Alzheimer's disease (AD). Methods A total of 372 individuals participating at the Dominantly Inherited Alzheimer Network study were examined to evaluate the cross‐sectional relationship of PA with cognitive performance, functional status, cognitive decline, and AD biomarkers in cerebrospinal fluid. Mutation carriers were categorized as high or low exercisers according to WHO recommendations. Results Mutation carriers with high PA showed significantly better cognitive and functional performance and significantly less AD‐like pathology in cerebrospinal fluid than individuals with low PA. Mutation carriers with high PA scored 3.4 points better on Mini Mental State Examination at expected symptom onset and fulfilled the diagnosis of very mild dementia 15.1 years later compared with low exercisers. Discussion These results support a beneficial effect of PA on cognition and AD pathology even in individuals with genetically driven autosomal dominant AD.

Introduction: The objective of this study was to evaluate the relationship between self-reported exercise levels and Alzheimer's disease (AD) biomarkers, in a cohort of autosomal dominant AD mutation carriers. Methods: In 139 presymptomatic mutation carriers from the Dominantly Inherited Alzheimer Network, the relationship between self-reported exercise levels and brain amyloid load, cerebrospinal fluid (CSF) Aβ42, and CSF tau levels was evaluated using linear regression. Results: No differences in brain amyloid load, CSF Aβ42, or CSF tau were observed between low and high exercise groups. Nevertheless, when examining only those already accumulating AD pathology (i.e., amyloid positive), low exercisers had higher mean levels of brain amyloid than high exercisers. Furthermore, the interaction between exercise and estimated years from expected symptom onset was a significant predictor of brain amyloid levels. Discussion: Our findings indicate a relationship exists between self-reported exercise levels and brain amyloid in autosomal dominant AD mutation carriers.

The relationship between body-mass index (BMI) and Alzheimer´s disease (AD) has been extensively investigated. However, BMI alterations in preclinical individuals with autosomal dominant AD (ADAD) have not yet been investigated. We analyzed cross-sectional data from 230 asymptomatic members of families with ADAD participating in the Dominantly Inherited Alzheimer Network (DIAN) study including 120 preclinical mutation carriers (MCs) and 110 asymptomatic non-carriers (NCs). Differences in BMI and their relation with cerebral amyloid load and episodic memory as a function of estimated years to symptom onset (EYO) were analyzed. Preclinical MCs showed significantly lower BMIs compared to NCs, starting 11.2 years before expected symptom onset. However, the BMI curves begun to diverge already at 17.8 years before expected symptom onset. Lower BMI in preclinical MCs was significantly associated with less years before estimated symptom onset, higher global Aβ brain burden, and with lower delayed total recall scores in the logical memory test. The study provides cross-sectional evidence that weight loss starts one to two decades before expected symptom onset of ADAD. Our findings point toward a link between the pathophysiology of ADAD and disturbance of weight control mechanisms. Longitudinal follow-up studies are warranted to investigate BMI changes over time.

Background and Objective: Aberrant lipid metabolism has been implicated in sporadic Alzheimer’s disease (AD). The current study investigated plasma phospholipid and sphingolipid profiles in individuals carrying PSEN1 mutations responsible for autosomal dominant AD (ADAD). Methods: Study participants evaluated were from the Perth and Melbourne sites of the Dominantly Inherited Alzheimer Network (DIAN) study. Plasma phospholipid and sphingolipid profiles were measured using liquid chromatography coupled with mass spectrometry in 20 PSEN1 mutation carriers (MC; eight of whom were symptomatic and twelve asymptomatic, based on Clinical Dementia Rating scores) and compared with six non carriers (NC) using linear mixed models. Further, AD gold standard biomarker data obtained from the DIAN database were correlated with lipid species significantly altered between MC and NC, using Spearman’s correlation coefficient. Results: One-hundred and thirty-nine plasma phospholipid and sphingolipid species were measured. Significantly altered species in MC compared to NC primarily belonged to choline and ethanolamine containing phospholipid classes and ceramides. Further phosphatidylcholine species (34:6, 36:5, 40:6) correlated with cerebrospinal fluid tau (p < 0.05), and plasmalogen ethanolamine species (34:2, 36:,4) correlated with both cerebrospinal fluid tau and brain amyloid load within the MC group (p < 0.05). Conclusion: These findings indicate altered phospholipid and sphingolipid metabolism in ADAD and provide insight into the pathomolecular changes occurring with ADAD pathogenesis. Further, findings reported in this study allow comparison of lipid alterations in ADAD with those reported previously in sporadic AD. The findings observed in the current pilot study warrant validation in the larger DIAN cohort.

Contains fulltext : 154021.pdf (publisher's version ) (Open Access), INTRODUCTION: Amyloid-beta (Abeta) has been investigated as a diagnostic biomarker and therapeutic drug target. Recent studies found that cerebrospinal fluid (CSF) Abeta fluctuates over time, including as a diurnal pattern, and increases in absolute concentration with serial collection. It is currently unknown what effect differences in CSF collection methodology have on Abeta variability. In this study, we sought to determine the effect of different collection methodologies on the stability of CSF Abeta concentrations over time. METHODS: Grouped analysis of CSF Abeta levels from multiple industry and academic groups collected by either lumbar puncture (n=83) or indwelling lumbar catheter (n=178). Participants were either placebo or untreated subjects from clinical drug trials or observational studies. Participants had CSF collected by lumbar puncture or lumbar catheter for quantitation of Abeta concentration by enzyme linked immunosorbent assay. Data from all sponsors was converted to percent of the mean for Abeta40 and Abeta42 for comparison. Repeated measures analysis of variance was performed to assess for factors affecting the linear rise of Abeta concentrations over time. RESULTS: Analysis of studies collecting CSF via lumbar catheter revealed tremendous inter-subject variability of Abeta40 and Abeta42 as well as an Abeta diurnal pattern in all of the sponsors' studies. In contrast, Abeta concentrations from CSF samples collected at two time points by lumbar puncture showed no significant differences. Repeated measures analysis of variance found that only time and draw frequency were significantly associated with the slope of linear rise in Abeta40 and Abeta42 concentrations during the first 6 hours of collection. CONCLUSIONS: Based on our findings, we recommend minimizing the frequency of CSF draws in studies measuring Abeta levels and keeping the frequency standardized between experimental groups. The Abeta diurnal pattern was noted in all sponsors' studies

Objective. We examined the diagnostic value of subjective memory complaints (SMCs) assessed with a single item in a large cross-sectional cohort consisting of families with autosomal dominant Alzheimer’s disease (ADAD) participating in the Dominantly Inherited Alzheimer Network (DIAN). Methods. The baseline sample of 183 mutation carriers (MCs) and 117 noncarriers (NCs) was divided according to Clinical Dementia Rating (CDR) scale into preclinical (CDR 0; MCs: n = 107; NCs: n = 109), early symptomatic (CDR 0.5; MCs: n = 48; NCs: n = 8), and dementia stage (CDR ≥ 1; MCs: n = 28; NCs: n = 0). These groups were subdivided by the presence or absence of SMCs. Results. At CDR 0, SMCs were present in 12.1% of MCs and 9.2% of NCs (P = 0.6). At CDR 0.5, SMCs were present in 66.7% of MCs and 62.5% of NCs (P = 1.0). At CDR ≥ 1, SMCs were present in 96.4% of MCs. SMCs in MCs were significantly associated with CDR, logical memory scores, Geriatric Depression Scale, education, and estimated years to onset. Conclusions: The present study shows that SMCs assessed by a single-item scale have no diagnostic value to identify preclinical ADAD in asymptomatic individuals. These results demonstrate the need of further improvement of SMC measures that should be examined in large clinical trials.

Introduction: This study examines platelet amyloid precursor protein (APP) isoform ratios of 120KDa to 110KDa (APPr) between mutation carriers (MC) carrying a mutation for autosomal dominant Alzheimer's disease (ADAD) and non-carriers (NC). Two previous studies reported no significant difference in APPr between ADAD MC and NC, which may have been due to the small sample size in both studies. The current study examines APPr in MC versus NC in a larger sample. In addition, it investigated whether APPr correlate with neuroimaging data, neuropsychological data and cerebrospinal fluid biomarkers in a cohort subset derived from the Dominantly Inherited Alzheimer Network (DIAN) study. Methods: APPr were quantified by western blotting. Fifteen MC (symptomatic and asymptomatic) were compared against twelve NC using univariate general linear model. All participants underwent neuroimaging and neuropsychological testing which were correlated with APPr using Pearson's correlation coefficient (r). Results: APPr were lower in MC compared to NC (p=0.003) while Mini-Mental State Examination (MMSE) scores were not significantly different (p>0.1). Furthermore, APPr inversely correlated with amyloid imaging in the Caudate Nucleus (r=-0.505; p<0.05) and Precuneus (r=-0.510; p<0.05). Conclusion: APPr are lower in ADAD MC compared to NC, and inversely correlated with brain amyloid load prior to significant differences in cognitive health. However, the use of APPr as a biomarker needs to be explored further.

The recent history of dryland farming in the Australian semi-arid tropics is discussed briefly against the background of national and state policies, established following World War II, aimed at increasing the population and development of northern Australia. Some reference is also made to irrigation as a means of overcoming limitations imposed by rainfall and to complement dryland farming systems. The environmental and socio-economic constraints whch have so far limited commercial agriculture in the Australian semi-arid tropics are highlighted. Efforts, particularly in north-west Australia, to develop sustainable farming systems based on legume pasture leys and livestock production in conjunction with annual cropping, as a basis for closer settlement, are reviewed. These attempts, which began in the 1960s and stemmed from earlier post-war agricultural research in the region, initially relied on a pasture legume (Stylosanthes humilis cv. Townsville stylo) and conventional tillage. Farming system development continues today using new legume species (e.g. Stylosanthes hamata cv. Verano and Centrosema pascuorum cv. Cavalcade) and no-tillage cropping technology. This paper documents the history of agricultural and research development, and commercial practice in the Australian semi-arid tropics.

The Boulder-Lefroy shear zone includes the districts of St Ives (253 t of contained Au), Hampton-Boulder-Jubilee (123 t), Golden Mile (1 821 t) plus Mount Charlotte (219 t) and Paddington-Broad Arrow (112 t). Structural studies showed that the shear zone system developed in two main stages, the first related to a phase of north-northwest-south-southeast-trending folding and thrusting and the second related to sinistral shearing that reactivated and linked the pre-existing north-northwest-south-southeast-trending network of thrust planes. Sinistral movement resulted in only limited displacement and evolved from a ductile shearing in a broad zone toward semi-brittle shearing along narrow planes. The structures suggest a temporal evolution from crustal thickening through lateral escape to the development of brittle structures. The Fimiston and Oroya lodes at the Golden Mile in Kalgoorlie were most likely developed during the first stage. Intense mineralisation within and around the shear zone resulted from multiscale focusing of mineralising fluids., The Boulder-Lefroy shear zone includes the districts of St Ives (253 t of contained Au), Hampton-Boulder-Jubilee (123 t), Golden Mile (1 821 t) plus Mount Charlotte (219 t) and Paddington-Broad Arrow (112 t). Structural studies showed that the shear zone system developed in two main stages, the first related to a phase of north-northwest-south-southeast-trending folding and thrusting and the second related to sinistral shearing that reactivated and linked the pre-existing north-northwest-south-southeast-trending network of thrust planes. Sinistral movement resulted in only limited displacement and evolved from a ductile shearing in a broad zone toward semi-brittle shearing along narrow planes. The structures suggest a temporal evolution from crustal thickening through lateral escape to the development of brittle structures. The Fimiston and Oroya lodes at the Golden Mile in Kalgoorlie were most likely developed during the first stage. Intense mineralisation within and around the shear zone resulted from multiscale focusing of mineralising fluids.