Search

BACKGROUND: The diagnosis of symptomatic Alzheimer's disease is a clinical challenge in adults with Down syndrome. Blood biomarkers would be of particular clinical importance in this population. The astrocytic Glial Fibrillary Acidic Protein (GFAP) is a marker of astrogliosis associated with amyloid pathology, but its longitudinal changes, association with other biomarkers and cognitive performance have not been studied in individuals with Down syndrome. METHODS: We performed a three-centre study of adults with Down syndrome, autosomal dominant Alzheimer's disease and euploid individuals enrolled in Hospital Sant Pau, Barcelona (Spain), Hospital Clinic, Barcelona (Spain) and Ludwig-Maximilians-Universität, Munich (Germany). Cerebrospinal fluid (CSF) and plasma GFAP concentrations were quantified using Simoa. A subset of participants had PET (18)F-fluorodeoxyglucose, amyloid tracers and MRI measurements. FINDINGS: This study included 997 individuals, 585 participants with Down syndrome, 61 Familial Alzheimer's disease mutation carriers and 351 euploid individuals along the Alzheimer's disease continuum, recruited between November 2008 and May 2022. Participants with Down syndrome were clinically classified at baseline as asymptomatic, prodromal Alzheimer's disease and Alzheimer's disease dementia. Plasma GFAP levels were significantly increased in prodromal and Alzheimer's disease dementia compared to asymptomatic individuals and increased in parallel to CSF Aβ changes, ten years prior to amyloid PET positivity. Plasma GFAP presented the highest diagnostic performance to discriminate symptomatic from asymptomatic groups (AUC = 0.93, 95% CI 0.9−0.95) and its concentrations were significantly higher in progressors vs non-progressors (p

Background Plasma biomarkers for Alzheimer’s disease (AD) have broad potential as screening tools in primary care and disease-modifying trials. Detecting elevated amyloid-β (Aβ) pathology to support trial recruitment or initiating Aβ-targeting treatments would be of critical value. In this study, we aimed to examine the robustness of plasma biomarkers to detect elevated Aβ pathology at different stages of the AD continuum. Beyond determining the best biomarker—or biomarker combination—for detecting this outcome, we also simulated increases in inter-assay coefficient of variability (CV) to account for external factors not considered by intra-assay variability. With this, we aimed to determine whether plasma biomarkers would maintain their accuracy if applied in a setting which anticipates higher variability (i.e., clinical routine). Methods We included 118 participants (cognitively unimpaired [CU, n = 50], cognitively impaired [CI, n = 68]) from the ADNI study with a full plasma biomarker profile (Aβ42/40, GFAP, p-tau181, NfL) and matched amyloid imaging. Initially, we investigated how simulated CV variations impacted single-biomarker discriminative performance of amyloid status. Then, we evaluated the predictive performance of models containing different biomarker combinations, based both on original and simulated measurements. Plasma Aβ42/40 was represented by both immunoprecipitation mass spectrometry (IP-MS) and single molecule array (Simoa) methods in separate analyses. Model selection was based on a decision tree which incorporated Akaike information criterion value, likelihood ratio tests between the best-fitting models and, finally, and Schwartz’s Bayesian information criterion. Results Increasing variation greatly impacted the performance of plasma Aβ42/40 in discriminating Aβ status. In contrast, the performance of plasma GFAP and p-tau181 remained stable with variations >20%. When biomarker models were compared, the models “AG” (Aβ42/40 + GFAP; AUC = 86.5), “A” (Aβ42/40; AUC = 82.3), and “AGP” (Aβ42/40 + GFAP + p-tau181; AUC = 93.5) were superior in determining Aβ burden in all participants, within-CU, and within-CI groups, respectively. In the robustness analyses, when repeating model selection based on simulated measurements, models including IP-MS Aβ42/40 were also most often selected. Simoa Aβ42/40 did not contribute to any selected model when used as an immunoanalytical alternative to IP-MS Aβ42/40. Conclusions Plasma Aβ42/40, as quantified by IP-MS, shows high performance in determining Aβ positivity at all stages of the AD continuum, with GFAP and p-tau181 further contributing at CI stage. However, between-assay variations greatly impacted the performance of Aβ42/40 but not that of GFAP and p-tau181. Therefore, when dealing with between-assay CVs that exceed 5%, plasma GFAP and p-tau181 should be considered for a more robust determination of Aβ burden in CU and CI participants, respectively.

IntroductionUnderstanding longitudinal plasma biomarker trajectories relative to brain amyloid changes can help devise Alzheimer’s progression assessment strategies.MethodsWe examined the temporal order of changes in plasma amyloid-β ratio (Aβ42/Aβ40), glial fibrillary acidic protein (GFAP), neurofilament light chain (NfL), and phosphorylated tau ratios (p-tau181/Aβ42, p-tau231/Aβ42) relative to11C-Pittsburgh compound B (PiB) positron emission tomography (PET) cortical amyloid burden (PiB−/+). Participants (n = 199) were cognitively normal at index visit with a median 6.1-year follow-up.ResultsPiB groups exhibited different rates of longitudinal change in Aβ42/Aβ40(β= 5.41 × 10-4, SE = 1.95 × 10-4,p= 0.0073). Change in brain amyloid correlated with change in GFAP (r= 0.5, 95% CI = [0.26, 0.68]). Greatest relative decline in Aβ42/Aβ40(-1%/year) preceded brain amyloid positivity by 41 years (95% CI = [32, 53]).DiscussionPlasma Aβ42/Aβ40may begin declining decades prior to brain amyloid accumulation, whereas p-tau ratios, GFAP, and NfL increase closer in time.

ImportanceThe recent proliferation of phosphorylated tau (p-tau) biomarkers has raised questions about their preferential association with the hallmark pathologies of Alzheimer disease (AD): amyloid-β plaques and tau neurofibrillary tangles.ObjectiveTo determine whether cerebrospinal fluid (CSF) and plasma p-tau biomarkers preferentially reflect cerebral β-amyloidosis or neurofibrillary tangle aggregation measured with positron emission tomography (PET).Design, Setting, and ParticipantsThis was a cross-sectional study of 2 observational cohorts: the Translational Biomarkers in Aging and Dementia (TRIAD) study, with data collected between October 2017 and August 2021, and the Alzheimer’s Disease Neuroimaging Initiative (ADNI), with data collected between September 2015 and November 2019. TRIAD was a single-center study, and ADNI was a multicenter study. Two independent subsamples were derived from TRIAD. The first TRIAD subsample comprised individuals assessed with CSF p-tau (p-tau181, p-tau217, p-tau231, p-tau235), [18F]AZD4694 amyloid PET, and [18F]MK6240 tau PET. The second TRIAD subsample included individuals assessed with plasma p-tau (p-tau181, p-tau217, p-tau231), [18F]AZD4694 amyloid PET, and [18F]MK6240 tau PET. An independent cohort from ADNI comprised individuals assessed with CSF p-tau181, [18F]florbetapir PET, and [18F]flortaucipir PET. Participants were included based on the availability of p-tau and PET biomarker assessments collected within 9 months of each other. Exclusion criteria were a history of head trauma or magnetic resonance imaging/PET safety contraindications. No participants who met eligibility criteria were excluded.ExposuresAmyloid PET, tau PET, and CSF and plasma assessments of p-tau measured with single molecule array (Simoa) assay or enzyme-linked immunosorbent assay.Main Outcomes and MeasuresAssociations between p-tau biomarkers with amyloid PET and tau PET.ResultsA total of 609 participants (mean [SD] age, 66.9 [13.6] years; 347 female [57%]; 262 male [43%]) were included in the study. For all 4 phosphorylation sites assessed in CSF, p-tau was significantly more closely associated with amyloid-PET values than tau-PET values (p-tau181 difference, 13%; 95% CI, 3%-22%; P = .006; p-tau217 difference, 11%; 95% CI, 3%-20%; P = .003; p-tau231 difference, 15%; 95% CI, 5%-22%; P 235 difference, 9%; 95% CI, 1%-19%; P = .02) . These results were replicated with plasma p-tau181 (difference, 11%; 95% CI, 1%-22%; P = .02), p-tau217 (difference, 9%; 95% CI, 1%-19%; P = .02), p-tau231 (difference, 13%; 95% CI, 3%-24%; P = .009), and CSF p-tau181 (difference, 9%; 95% CI, 1%-21%; P = .02) in independent cohorts.Conclusions and RelevanceResults of this cross-sectional study of 2 observational cohorts suggest that the p-tau abnormality as an early event in AD pathogenesis was associated with amyloid-β accumulation and highlights the need for careful interpretation of p-tau biomarkers in the context of the amyloid/tau/neurodegeneration, or A/T/(N), framework.

Introduction: There is increasing evidence that phosphorylated tau (P-tau181) is a specific biomarker for Alzheimer's disease (AD) pathology, but its potential utility in non-White patient cohorts and patients with concomitant cerebrovascular disease (CeVD) is unknown. Methods: Single molecule array (Simoa) measurements of plasma P-tau181, total tau, amyloid beta (Aβ)40 and Aβ42, as well as derived ratios were correlated with neuroimaging modalities indicating brain amyloid (Aβ+), hippocampal atrophy, and CeVD in a Singapore-based cohort of non-cognitively impaired (NCI; n = 43), cognitively impaired no dementia (CIND; n = 91), AD (n = 44), and vascular dementia (VaD; n = 22) subjects. Results: P-tau181/Aβ42 ratio showed the highest area under the curve (AUC) for Aβ+ (AUC = 0.889) and for discriminating between AD Aβ+ and VaD Aβ− subjects (AUC = 0.903). In addition, P-tau181/Aβ42 ratio was associated with hippocampal atrophy. None of the biomarkers was associated with CeVD. Discussion: Plasma P-tau181/Aβ42 ratio may be a noninvasive means of identifying AD with elevated brain amyloid in populations with concomitant CeVD.

Purpose The development of blood biomarkers that reflect Alzheimer’s disease (AD) pathophysiology (phosphorylated tau and amyloid-β) has offered potential as scalable tests for dementia differential diagnosis and early detection. In 2019, the Geneva AD Biomarker Roadmap Initiative included blood biomarkers in the systematic validation of AD biomarkers. Methods A panel of experts convened in November 2019 at a two-day workshop in Geneva. The level of maturity (fully achieved, partly achieved, preliminary evidence, not achieved, unsuccessful) of blood biomarkers was assessed based on the Biomarker Roadmap methodology and discussed fully during the workshop which also evaluated cerebrospinal fluid (CSF) and positron emission tomography (PET) biomarkers. Results Plasma p-tau has shown analytical validity (phase 2 primary aim 1) and first evidence of clinical validity (phase 3 primary aim 1), whereas the maturity level for Aβ remains to be partially achieved. Full and partial achievement has been assigned to p-tau and Aβ, respectively, in their associations to ante-mortem measures (phase 2 secondary aim 2). However, only preliminary evidence exists for the influence of covariates, assay comparison and cut-off criteria. Conclusions Despite the relative infancy of blood biomarkers, in comparison to CSF biomarkers, much has already been achieved for phases 1 through 3 – with p-tau having greater success in detecting AD and predicting disease progression. However, sufficient data about the effect of covariates on the biomarker measurement is lacking. No phase 4 (real-world performance) or phase 5 (assessment of impact/cost) aim has been tested, thus not achieved.

Introduction This study investigated the diagnostic and disease‐monitoring potential of plasma biomarkers in mild cognitive impairment (MCI) and Alzheimer's disease (AD) dementia and cognitively unimpaired (CU) individuals. Methods Plasma was analyzed using Simoa assays from 99 CU, 107 MCI, and 103 AD dementia participants. Results Phosphorylated‐tau181 (P‐tau181), neurofilament light, amyloid‐β (Aβ42/40), Total‐tau and Glial fibrillary acidic protein were altered in AD dementia but P‐tau181 significantly outperformed all biomarkers in differentiating AD dementia from CU (area under the curve [AUC] = 0.91). P‐tau181 was increased in MCI converters compared to non‐converters. Higher P‐tau181 was associated with steeper cognitive decline and gray matter loss in temporal regions. Longitudinal change of P‐tau181 was strongly associated with gray matter loss in the full sample and with Aβ measures in CU individuals. Discussion P‐tau181 detected AD at MCI and dementia stages and was strongly associated with cognitive decline and gray matter loss. These findings highlight the potential value of plasma P‐tau181 as a non‐invasive and cost‐effective diagnostic and prognostic biomarker in AD.

Alzheimer’s Disease Neuroimaging Initiative., Tau phosphorylated at threonine 181 (p-tau181) measured in blood plasma has recently been proposed as an accessible, scalable, and highly specific biomarker for Alzheimer’s disease. Longitudinal studies, however, investigating the temporal dynamics of this novel biomarker are lacking. It is therefore unclear when in the disease process plasma p-tau181 increases above physiological levels and how it relates to the spatiotemporal progression of Alzheimer’s disease characteristic pathologies. We aimed to establish the natural time course of plasma p-tau181 across the sporadic Alzheimer’s disease spectrum in comparison to those of established imaging and fluid-derived biomarkers of Alzheimer’s disease. We examined longitudinal data from a large prospective cohort of elderly individuals enrolled in the Alzheimer’s Disease Neuroimaging Initiative (ADNI) (n = 1067) covering a wide clinical spectrum from normal cognition to dementia, and with measures of plasma p-tau181 and an 18F-florbetapir amyloid-β PET scan at baseline. A subset of participants (n = 864) also had measures of amyloid-β1–42 and p-tau181 levels in CSF, and another subset (n = 298) had undergone an 18F-flortaucipir tau PET scan 6 years later. We performed brain-wide analyses to investigate the associations of plasma p-tau181 baseline levels and longitudinal change with progression of regional amyloid-β pathology and tau burden 6 years later, and estimated the time course of changes in plasma p-tau181 and other Alzheimer’s disease biomarkers using a previously developed method for the construction of long-term biomarker temporal trajectories using shorter-term longitudinal data. Smoothing splines demonstrated that earliest plasma p-tau181 changes occurred even before amyloid-β markers reached abnormal levels, with greater rates of change correlating with increased amyloid-β pathology. Voxel-wise PET analyses yielded relatively weak, yet significant, associations of plasma p-tau181 with amyloid-β pathology in early accumulating brain regions in cognitively healthy individuals, while the strongest associations with amyloid-β were observed in late accumulating regions in patients with mild cognitive impairment. Cross-sectional and particularly longitudinal measures of plasma p-tau181 were associated with widespread cortical tau aggregation 6 years later, covering temporoparietal regions typical for neurofibrillary tangle distribution in Alzheimer’s disease. Finally, we estimated that plasma p-tau181 reaches abnormal levels ∼6.5 and 5.7 years after CSF and PET measures of amyloid-β, respectively, following similar dynamics as CSF p-tau181. Our findings suggest that plasma p-tau181 increases are associated with the presence of widespread cortical amyloid-β pathology and with prospective Alzheimer’s disease typical tau aggregation, providing clear implications for the use of this novel blood biomarker as a diagnostic and screening tool for Alzheimer’s disease., M.J.G. is supported by the “Miguel Servet” program [CP19/00031] of the Spanish Instituto de Salud Carlos III (ISCIII-FEDER). T.K.K. holds a research fellowship from the Brightfocus Foundation (#A2020812F), and is further supported by the Swedish Alzheimer Foundation (Alzheimerfonden; #AF-930627), the Swedish Brain Foundation (Hjärnfonden; #FO2020-0240), the Swedish Dementia Foundation (Demensförbundet), the Agneta Prytz-Folkes & Gösta Folkes Foundation (#2020-00124), the Aina (Ann) Wallströms and Mary-Ann Sjöbloms Foundation, the Anna Lisa and Brother Björnsson’s Foundation, Gamla Tjänarinnor, and the Gun and Bertil Stohnes Foundation. A.S. is supported by the Paulo Foundation and the Orion Research Foundation. M.S.C. received funding from the European Union’s Horizon 2020 Research and Innovation Program under the Marie Sklodowska-Curie action grant agreement No 752310, and currently receives funding from Instituto de Salud Carlos III (PI19/00155) and from the Spanish Ministry of Science, Innovation and Universities (Juan de la Cierva Programme grant IJC2018-037478-I). H.Z. is a Wallenberg Scholar supported by grants from the Swedish Research Council (#2018-02532), the European Research Council (#681712), Swedish State Support for Clinical Research (#ALFGBG-720931), the Alzheimer Drug Discovery Foundation (ADDF), USA (#201809-2016862), and the UK Dementia Research Institute at UCL. K.B. is supported by the Swedish Research Council (#2017-00915), the Alzheimer Drug Discovery Foundation (ADDF), USA (#RDAPB-201809-2016615), the Swedish Alzheimer Foundation (#AF-742881), Hjärnfonden, Sweden (#FO2017-0243), the Swedish state under the agreement between the Swedish government and the County Councils, the ALF-agreement (#ALFGBG-715986), and European Union Joint Program for Neurodegenerative Disorders (JPND2019-466-236). M.S. is supported by the Knut and Alice Wallenberg Foundation (Wallenberg Centre for Molecular and Translational Medicine; KAW 2014.0363), the Swedish Research Council (#2017-02869), the Swedish state under the agreement between the Swedish government and the County Councils, the ALF-agreement (#ALFGBG-813971), and the Swedish Alzheimer Foundation (#AF-740191). Data collection and sharing for this project was funded by the Alzheimer's Disease Neuroimaging Initiative (ADNI) (National Institutes of Health Grant U01 AG024904) and DOD ADNI (Department of Defense award number W81XWH-12-2-0012). ADNI is funded by the National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering, and through generous contributions from the following: AbbVie, Alzheimer’s Association; Alzheimer’s Drug Discovery Foundation; Araclon Biotech; BioClinica, Inc.; Biogen; Bristol-Myers Squibb Company; CereSpir, Inc.; Cogstate; Eisai Inc.; Elan Pharmaceuticals, Inc.; Eli Lilly and Company; EuroImmun; F. Hoffmann-La Roche Ltd and its affiliated company Genentech, Inc.; Fujirebio; GE Healthcare; IXICO Ltd.; Janssen Alzheimer Immunotherapy Research & Development, LLC.; Johnson & Johnson Pharmaceutical Research & Development LLC.; Lumosity; Lundbeck; Merck & Co., Inc.; Meso Scale Diagnostics, LLC.; NeuroRx Research; Neurotrack Technologies; Novartis Pharmaceuticals Corporation; Pfizer Inc.; Piramal Imaging; Servier; Takeda Pharmaceutical Company; and Transition Therapeutics. The Canadian Institutes of Health Research is providing funds to support ADNI clinical sites in Canada.

Summary: Background: Phosphorylated tau (p-tau) epitopes in cerebrospinal fluid (CSF) are accurate biomarkers for a pathological and clinical diagnosis of Alzheimer's disease (AD) and are seen to be increased in preclinical stage of the disease. However, it is unknown if these increases transpire earlier, prior to amyloid-beta (Aβ) positivity as determined by position emission tomography (PET), and if an ordinal sequence of p-tau epitopes occurs at this incipient phase Methods: We measured CSF concentrations of p-tau181, p-tau217 and p-tau231 in 171 participants across the AD continuum who had undergone Aβ ([18F]AZD4694) and tau ([18F]MK6240) position emission tomography (PET) and clinical assessment Findings: All CSF p-tau biomarkers were accurate predictors of cognitive impairment but CSF p-tau217 demonstrated the largest fold-changes in AD patients in comparison to non-AD dementias and cognitively unimpaired individuals. CSF p-tau231 and p-tau217 predicted Aβ and tau to a similar degree but p-tau231 attained abnormal levels first. P-tau231 was sensitive to the earliest changes of Aβ in the medial orbitofrontal, precuneus and posterior cingulate before global Aβ PET positivity was reached Interpretation: We demonstrate that CSF p-tau231 increases early in development of AD pathology and is a principal candidate for detecting incipient Aβ pathology for therapeutic trial application Funding: Canadian Institutes of Health Research (CIHR), Canadian Consortium of Neurodegeneration and Aging, Weston Brain Institute, Brain Canada Foundation, the Fonds de Recherche du Québec.

Summary: Background: Tau in Alzheimer's disease (AD) is assessed via cerebrospinal fluid (CSF) and Positron emission tomography (PET). Novel methods to detect phosphorylated tau (pTau) in blood have been recently developed. We aim to investigate agreement of tau status as determined by [18F]MK6240 tau-PET, plasma pTau181 and pTau231. Methods: We assessed cognitively unimpaired young, cognitively unimpaired, mild cognitive impairment and AD individuals with [18F]MK6240, plasma pTau181, pTau 231, [18F]AZD4694 amyloid-PET and MRI. A subset underwent CSF assessment.We conducted ROC curves to obtain cut-off values for plasma pTau epitopes. Individuals were categorized as positive or negative in all biomarkers. We then compared the distribution among concordant and discordant groups in relation to diagnosis, Aβ status, APOEε4 status, [18F]AZD4694 global SUVR, hippocampal volume and CSF pTau181. Findings: The threshold for positivity was 15.085 pg/mL for plasma pTau181 and 17.652 pg/mL for plasma pTau231. Most individuals had concordant statuses, however, 18% of plasma181/PET, 26% of plasma231/PET and 25% of the pTau231/pTau181 were discordant. Positivity to at least one biomarker was often accompanied by diagnosis of cognitive impairment, Aβ positivity, APOEε4 carriership, higher levels of [18F]AZD4694 global SUVR, hippocampal atrophy and CSF pTau181. Interpretation: Plasma pTau181, pTau231 and [18F]MK6240 seem to reflect different stages of tau progression. Plasma biomarkers can be useful in the context of diagnostic information and clinical trials, to evaluate the disease stage. Moreover, they seem to confidently evaluate tau-PET positivity. Funding: Moreover, this study was supported by Weston Brain Institute, Canadian Institute of Health Research and Fonds de Recherche du Québec.

Alzheimer’s disease is the leading cause of dementia worldwide and is characterized by a long preclinical phase in which amyloid-β and tau accumulate in the absence of cognitive decline. In vivo biomarkers for Alzheimer’s disease are expensive, invasive and inaccessible, yet are critical for accurate disease diagnosis and patient management. Recent ultrasensitive methods to measure plasma phosphorylated tau 181 (p-tau181) display strong correlations with tau positron emission tomography, p-tau181 in CSF, and tau pathology at autopsy. The clinical utility of plasma-based p-tau181 biomarkers is unclear. In a longitudinal multicentre observational study, we assessed 1113 non-demented individuals (509 cognitively unimpaired elderly and 604 individuals with mild cognitive impairment) from the Alzheimer’s Disease Neuroimaging Initiative who underwent neuropsychological assessments and were evaluated for plasma p-tau181. The primary outcome was a memory composite z-score. Mixed-effect models assessed rates of memory decline in relation to baseline plasma p-tau181, and whether plasma p-tau181 significantly predicted memory decline beyond widely available clinical and genetic data (age, sex, years of education, cardiovascular and metabolic conditions, and APOEε4 status). Participants were followed for a median of 4.1 years. Baseline plasma p-tau181 was associated with lower baseline memory (β estimate: −0.49, standard error: 0.06, t-value: −7.97), as well as faster rates of memory decline (β estimate: −0.11, standard error: 0.01, t-value: −7.37). Moreover, the inclusion of plasma p-tau181 resulted in improved prediction of memory decline beyond clinical and genetic data (marginal R2 of 16.7–23%, χ2 = 100.81, P, Therriault et al. report that a plasma-based biomarker for phosphorylated tau was associated with memory decline. This biomarker could help predict future cognitive decline associated with Alzheimer’s disease in people who have mild cognitive symptoms, or no symptoms at all., Graphical Abstract Graphical Abstract

Alzheimer’s disease biomarkers are primarily evaluated through MRI, PET and CSF methods in order to diagnose and monitor disease. Recently, advances in the assessment of blood-based biomarkers have shown promise for simple, inexpensive, accessible and minimally invasive tools with diagnostic and prognostic value for Alzheimer’s disease. Most recently, plasma phosphorylated tau181 has shown excellent performance. The relationship between plasma phosphorylated tau181 and cerebral metabolic dysfunction assessed by [18F]fluorodeoxyglucose PET in Alzheimer’s disease is still unknown. This study was performed on 892 older individuals (297 cognitively unimpaired; 595 cognitively impaired) from the Alzheimer’s Disease Neuroimaging Initiative cohort. Plasma phosphorylated tau181 was assessed using single molecular array technology and metabolic dysfunction was indexed by [18F]fluorodeoxyglucose PET. Cross-sectional associations between plasma and CSF phosphorylated tau181 and [18F]fluorodeoxyglucose were assessed using voxelwise linear regression models, with individuals stratified by diagnostic group and by β-amyloid status. Associations between baseline plasma phosphorylated tau181 and longitudinal (24 months) rate of brain metabolic decline were also assessed in 389 individuals with available data using correlations and voxelwise regression models. Plasma phosphorylated tau181 was elevated in β-amyloid positive and cognitively impaired individuals as well as in apolipoprotein E ε4 carriers and was significantly associated with age, worse cognitive performance and CSF phosphorylated tau181. Cross-sectional analyses showed strong associations between plasma phosphorylated tau181 and [18F]fluorodeoxyglucose PET in cognitively impaired and β-amyloid positive individuals. Voxelwise longitudinal analyses showed that baseline plasma phosphorylated tau181 concentrations were significantly associated with annual rates of metabolic decline in cognitively impaired individuals, bilaterally in the medial and lateral temporal lobes. The associations between plasma phosphorylated tau181 and reduced brain metabolism, primarily in cognitively impaired and in β-amyloid positive individuals, supports the use of plasma phosphorylated tau181 as a simple, low-cost, minimally invasive and accessible tool to both assess current and predict future metabolic dysfunction associated with Alzheimer’s disease, comparatively to PET, MRI and CSF methods., Graphical Abstract Graphical Abstract, Lussier et al. report that plasma phosphorylated tau181 is associated cross-sectionally with CSF phosphorylated tau181 and [18F]fluorodeoxyglucose PET in 823 individuals from the Alzheimer’s Disease Neuroimaging Initiative cohort. The authors also report a significant association between baseline plasma p-tau181 and longitudinal change in brain glucose metabolism indexed by [18F]fluorodeoxyglucose PET.

Extracts of the tropical Cinderella plantSynedrella nodifloraare used traditionally to manage convulsive conditions in the West African sub-region. This study sought to determine the neuronal basis of the effectiveness of these plant extracts to suppress seizure activity. Using the hippocampal slice preparation from rats, the ability of the extract to depress excitatory synaptic transmission andin vitroseizure activity were investigated. Bath perfusion of the hydro-ethanolic extract ofSynedrella nodiflora(SNE) caused a concentration-dependent depression of evoked field excitatory postsynaptic potentials (fEPSPs) recorded extracellularly in the CA1 region of the hippocampus with maximal depression of about 80% and an estimated IC50of 0.06 mg/ml. The SNE-induced fEPSP depression was accompanied by an increase in paired pulse facilitation. The fEPSP depression only recovered partially after 20 min washing out. The effect of SNE was not stimulus dependent as it was present even in the absence of synaptic stimulation. Furthermore, it did not show desensitization as repeat application after 10 min washout produced the same level of fEPSP depression as the first application. The SNE effect on fEPSPs was not via adenosine release as it was neither blocked nor reversed by 8-CPT, an adenosine A1receptor antagonist. In addition, SNE depressedin vitroseizures induced by zero Mg2+and high K+-containing artificial cerebrospinal fluid (aCSF) in a concentration-dependent manner. The results show that SNE depresses fEPSPs and spontaneous bursting activity in hippocampal neurons that may underlie its ability to abort convulsive activity in persons with epilepsy.

Background Recent studies suggest that plasma phosphorylated tau181 (p-tau181) is a highly specific biomarker for Alzheimer’s disease (AD)-related tau pathology. It has great potential for the diagnostic and prognostic evaluation of AD, since it identifies AD with the same accuracy as tau PET and CSF p-tau181 and predicts the development of AD dementia in cognitively unimpaired (CU) individuals and in those with mild cognitive impairment (MCI). Plasma p-tau181 may also be used as a biomarker in studies exploring disease pathogenesis, such as genetic or environmental risk factors for AD-type tau pathology. The aim of the present study was to investigate the relation between polygenic risk scores (PRSs) for AD and plasma p-tau181. Methods Data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) was used to examine the relation between AD PRSs, constructed based on findings in recent genome-wide association studies, and plasma p-tau181, using linear regression models. Analyses were performed in the total sample (n = 818), after stratification on diagnostic status (CU (n = 236), MCI (n = 434), AD dementia (n = 148)), and after stratification on Aβ pathology status (Aβ positives (n = 322), Aβ negatives (n = 409)). Results Associations between plasma p-tau181 and APOE PRSs (p = 3e−18–7e−15) and non-APOE PRSs (p = 3e−4–0.03) were seen in the total sample. The APOE PRSs were associated with plasma p-tau181 in all diagnostic groups (CU, MCI, and AD dementia), while the non-APOE PRSs were associated only in the MCI group. The APOE PRSs showed similar results in amyloid-β (Aβ)-positive and negative individuals (p = 5e−5–1e−3), while the non-APOE PRSs were associated with plasma p-tau181 in Aβ positives only (p = 0.02). Conclusions Polygenic risk for AD including APOE was found to associate with plasma p-tau181 independent of diagnostic and Aβ pathology status, while polygenic risk for AD beyond APOE was associated with plasma p-tau181 only in MCI and Aβ-positive individuals. These results extend the knowledge about the relation between genetic risk for AD and p-tau181, and further support the usefulness of plasma p-tau181 as a biomarker of AD.

Alzheimer’s disease (AD) is characterised by a long preclinical phase. Although phosphorylated tau (p‐tau) species such as p‐tau217 and p‐tau231 provide accurate detection of early pathological changes, other biomarkers capable of staging disease progression during preclinical AD are still needed. Combining exploratory and targeted mass spectrometry methods in neuropathologically confirmed brain tissue, we observed that p‐tau235 is a prominent feature of AD pathology. In addition, p‐tau235 seemed to be preceded by p‐tau231, in what appeared to be a sequential phosphorylation event. To exploit its biomarker potential in cerebrospinal fluid (CSF), we developed and validated a new p‐tau235 Simoa assay. Using three clinical cohorts, we demonstrated that (i) CSF p‐235 increases early in AD continuum, and (ii) changes in CSF p‐tau235 and p‐tau231 levels during preclinical AD are consistent with the sequential phosphorylation evidence in AD brain. In conclusion, CSF p‐tau235 appears to be not only a highly specific biomarker of AD but also a promising staging biomarker for the preclinical phase. Thus, it could prove useful tracking disease progression and help enriching clinical trial recruitment., A combination of mass spectrometry analysis of brain tissue and ultrasensitive immunoassays in three independent CSF cohorts identifies p‐tau235 as a novel biomarker for Alzheimer's disease (AD) – from preclinical stages to dementia.

In Alzheimer’s disease (AD), tau phosphorylation in the brain and its subsequent release into cerebrospinal fluid (CSF) and blood is a dynamic process that changes during disease evolution. The main aim of our study was to characterize the pattern of changes in phosphorylated tau (p‐tau) in the preclinical stage of the Alzheimer’s continuum. We measured three novel CSF p‐tau biomarkers, phosphorylated at threonine‐181 and threonine‐217 with an N‐terminal partner antibody and at threonine‐231 with a mid‐region partner antibody. These were compared with an automated mid‐region p‐tau181 assay (Elecsys) as the gold standard p‐tau measure. We demonstrate that these novel p‐tau biomarkers increase more prominently in preclinical Alzheimer, when only subtle changes of amyloid‐β (Aβ) pathology are detected, and can accurately differentiate Aβ‐positive from Aβ‐negative cognitively unimpaired individuals. Moreover, we show that the novel plasma N‐terminal p‐tau181 biomarker is mildly but significantly increased in the preclinical stage. Our results support the idea that early changes in neuronal tau metabolism in preclinical Alzheimer, likely in response to Aβ exposure, can be detected with these novel p‐tau assays., This study investigated novel CSF and plasma p‐tau biomarkers in the preclinical stage of the Alzheimer’s continuum and compared them with the widely used CSF Mid‐ptau181.

Tau neurofibrillary tangles are key pathological features of Alzheimer’s disease and other tauopathies. Recombinant protein technology is vital for studying the structure and function of tau in physiology and aggregation in pathophysiology. However, open-source and well-characterized plasmids for efficiently expressing and purifying different tau variants are lacking. We generated 44 sequence-verified plasmids including those encoding full length (FL) tau-441, its four-repeat microtubule-binding (K18) fragment, and their respective selected familial pathological variants (N279K, V337M, P301L, C291R, and S356T). Moreover, plasmids for expressing single (C291A), double (C291A/C322A), and triple (C291A/C322A/I260C) cysteine-modified variants were generated to study alterations in cysteine content and locations. Furthermore, protocols for producing representative tau forms were developed. We produced and characterized the aggregation behavior of the triple cysteine-modified tau-K18, often used in real-time cell internalization and aggregation studies because it can be fluorescently labeled on a cysteine outside the microtubule-binding core. Similar to the wild type (WT), triple cysteine-modified tau-K18 aggregated by progressive β-sheet enrichment, albeit at a slower rate. On prolonged incubation, cysteine-modified K18 formed paired helical filaments similar to those in Alzheimer’s disease, sharing morphological phenotypes with WT tau-K18 filaments. Nonetheless, cysteine-modified tau-K18 filaments were significantly shorter (p = 0.002) and mostly wider than WT filaments, explainable by their different principal filament elongation pathways: vertical (end-to-end) and lateral growth for WT and cysteine-modified, respectively. Cysteine rearrangement may therefore induce filament polymorphism. Together, the plasmid library, the protein production methods, and the new insights into cysteine-dependent aggregation should facilitate further studies and the design of antiaggregation agents.\ud \ud

Whilst cerebrospinal fluid (CSF) and positron emission tomography (PET) biomarkers for amyloid-β (Aβ) and tau pathologies are accurate for the diagnosis of Alzheimer’s disease (AD), their broad implementation in clinical and trial settings are restricted by high cost and limited accessibility. Plasma phosphorylated-tau181 (p-tau181) is a promising blood-based biomarker that is specific for AD, correlates with cerebral Aβ and tau pathology, and predicts future cognitive decline. In this study, we report the performance of p-tau181 in >1,000 individuals from the Alzheimer’s Disease Neuroimaging Initiative (ADNI), including cognitively unimpaired (CU), mild cognitive impairment (MCI) and AD dementia patients characterized by Aβ PET. We confirmed that plasma p-tau181 is increased at the preclinical stage of Alzheimer and further increases in MCI and AD dementia. Individuals clinically classified as AD dementia but having negative Aβ PET scans did not show increased plasma p-tau181. Despite being a multicenter study, plasma p-tau181 demonstrated high diagnostic accuracy to identify AD dementia (AUC=85.3%; 95% CI, 81.4%-89.2%), as well as to distinguish between Aβ- and Aβ+ individuals along the Alzheimer’scontinuum(AUC=76.9%; 95% CI, 74.0%-79.8%). Higher baseline concentrations of plasma p-tau181 accurately predicted future dementia and performed comparably to the baseline prediction of CSF p-tau181. Longitudinal measurements of plasma p-tau181 revealed low intra-individual variability, which could be of potential benefit in disease-modifying trials seeking a measurable response to a therapeutic target. This study adds significant weight to the growing body of evidence in the use of plasma p-tau181 as a non-invasive diagnostic and prognostic tool for AD, regardless of clinical stage, which would be of great benefit in clinical practice and a large cost-saving in clinical trial recruitment.

Blood biomarkers have great potential to advance clinical care and accelerate trials in Alzheimer’s disease (AD). Plasma phospho-tau181 (p-tau181) is a promising blood biomarker however, it is unknown if levels increase in presymptomatic AD. Therefore, we investigated the timing of p-tau181 changes using 153 blood samples from 70 individuals in a longitudinal study of familial AD (FAD). Plasma p-tau181 was measured, using an in-house single molecule array assay. We compared p-tau181 between symptomatic carriers, presymptomatic carriers, and non-carriers, adjusting for age and sex. We examined the relationship between p-tau181 and neurofilament light and estimated years to/from symptom onset (EYO), as well as years to/from actual onset in a symptomatic subgroup. In addition, we studied associations between p-tau181 and clinical severity, as well testing for differences between genetic subgroups. Twenty-four were presymptomatic carriers (mean baseline EYO −9.6 years) while 27 were non-carriers. Compared with non-carriers, plasma p-tau181 concentration was higher in both symptomatic (p

Tau is a predominantly neuronal protein that is normally bound to microtubules, where it acts to modulate neuronal and axonal stability. In humans, pathological forms of tau are implicated in a range of diseases that are collectively known as tauopathies. Kinases and phosphatases are responsible for maintaining the correct balance of tau phosphorylation to enable axons to be both stable and labile enough to function properly. In the early stages of tauopathies, this balance is interrupted leading to dissociation of tau from microtubules. This leaves microtubules prone to damage and phosphorylated tau prone to aggregation. Initially, phosphorylated tau forms oligomers, then fibrils, and ultimately neurofibrillary tangles (NFTs). It is widely accepted that the initial soluble oligomeric forms of tau are probably the most pathologically relevant species but there is relatively little quantitative information to explain exactly what their toxic effects are at the individual neuron level. Electrophysiology provides a valuable tool to help uncover the mechanisms of action of tau oligomers on synaptic transmission within single neurons. Understanding the concentration-, time-, and neuronal compartment-dependent actions of soluble tau oligomers on neuronal and synaptic properties are essential to understanding how best to counteract its effects and to develop effective treatment strategies. Here, we briefly discuss the standard approaches used to elucidate these actions, focusing on the advantages and shortcomings of the experimental procedures. Subsequently, we will describe a new approach that addresses specific challenges with the current methods, thus allowing real-time toxicity evaluation at the single-neuron level.\ud \ud

Background: It is still unknown if serum glial fibrillary acidic protein (GFAP) is a useful marker in frontotemporal lobar degeneration (FTLD). Objective: To assess the diagnostic and prognostic value of serum GFAP in a large cohort of patients with FTLD. Methods: In this retrospective study, performed on 406 participants, we measured serum GFAP concentration with an ultrasensitive Single molecule array (Simoa) method in patients with FTLD, Alzheimer’s disease (AD), and in cognitively unimpaired elderly controls. We assessed the role of GFAP as marker of disease severity by analyzing the correlation with clinical variables, neurophysiological data, and cross-sectional brain imaging. Moreover, we evaluated the role of serum GFAP as a prognostic marker of disease survival. Results: We observed significantly higher levels of serum GFAP in patients with FTLD syndromes, except progressive supranuclear palsy, compared with healthy controls, but not compared with AD patients. In FTLD, serum GFAP levels correlated with measures of cognitive dysfunction and disease severity, and were associated with indirect measures of GABAergic deficit. Serum GFAP concentration was not a significant predictor of survival. Conclusion: Serum GFAP is increased in FTLD, correlates with cognition and GABAergic deficits, and thus shows promise as a biomarker of disease severity in FTLD.

The neuropathological confirmation of amyloid-β (Aβ) plaques and tau neurofibrillary tangles (NFT) remains the gold standard for a definitive diagnosis of Alzheimer's disease (AD). Nowadays, the in vivo diagnosis of AD is greatly aided by both cerebrospinal fluid (CSF) and positron emission tomography (PET) biomarkers. Although highly accurate, their broad implementation is restricted by high cost, limited accessibility and invasiveness. We recently developed a high-performance, ultrasensitive immunoassay for the quantification of tau phosphorylated at threonine-181 (p-tau181) in plasma, which identifies AD pathophysiology with high accuracy. However, it remains unclear whether plasma p-tau181, measured years before the death, can predict the eventual neuropathological confirmation of AD, and successfully discriminates AD from non-AD dementia pathologies. We studied a unique cohort of 115 individuals with longitudinal blood collections with clinical evaluation at 8, 4 and 2 years prior to neuropathological assessment at death. The results demonstrate that plasma p-tau181 associates better with AD neuropathology and Braak staging than a clinical diagnosis 8 years before post-mortem. Moreover, while all patients had a diagnosis of AD dementia during life, plasma p-tau181 proved to discriminate AD from non-AD pathologies with high accuracy (AUC = 97.4%, 95% CI = 94.1-100%) even 8 years before death. Additionally, the longitudinal trajectory of plasma p-tau181 was assessed in all patients. We found that the main increases in plasma p-tau181 occurred between 8 and 4 years prior to death in patients with AD neuropathology and later plateauing. In contrast, non-AD pathologies and controls exhibited minor, albeit significant, increases in p-tau181 up until death. Overall, our study demonstrates that plasma p-tau181 is highly predictive and specific of AD neuropathology years before post-mortem examination. These data add further support for the use of plasma p-tau181 to aid clinical management in primary care and recruitment for clinical trials. Open access funding provided by University of Gothenburg. This study represents independent research partly funded by the National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King’s College London. Tissue samples were supplied by The London Neurodegenerative Diseases Brain Bank, which receives funding from the UK Medical Research Council and as part of the Brains for Dementia Research programme, jointly funded by Alzheimer’s Research UK and the Alzheimer’s Society. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health. The datasets used and/or analysed during the current study available from the corresponding author on reasonable request. TKK holds a postdoctoral fellowship from the BrightFocus Foundation (#A2020812F), and was further supported by the Swedish Alzheimer Foundation (Alzheimerfonden; #AF-930627), the Swedish Brain Foundation (Hjärnfonden; #FO2020-0240), the Swedish Dementia Foundation (Demensförbundet), the Agneta Prytz-Folkes and Gösta Folkes Foundation, Gamla Tjänarinnor, the Aina (Ann) Wallströms and Mary-Ann Sjöbloms Foundation, the Gun and Bertil Stohnes Foundation, and the Anna Lisa and Brother Björnsson’s Foundation. MSC received funding from the European Union’s Horizon 2020 Research and Innovation Program under the Marie Sklodowska-Curie action grant agreement no. 752310, and currently receives funding from Instituto de Salud Carlos III (PI19/00155) and from the Spanish Ministry of Science, Innovation and Universities (Juan de la Cierva Programme grant IJC2018-037478-I). AH is funded by Research Centre for Mental Health and Biomedical Research Unit for Dementia. KB holds the Torsten Söderberg Professorship in Medicine and is supported by grants from the Swedish Research Council, the Swedish Alzheimer Foundation, and the Swedish Brain Foundation. AH is funded by Research Centre for Mental Health and Biomedical Research Unit for Dementia. KB holds the Torsten Söderberg Professorship in Medicine and is supported by grants from the Swedish Research Council, the Swedish Alzheimer Foundation, and the Swedish Brain Foundation. KB holds the Torsten Söderberg Professorship in Medicine at the Royal Swedish Academy of Sciences, and is supported by the Swedish Research Council (#2017-00915), the Swedish Alzheimer Foundation (#AF-742881), Hjärnfonden, Sweden (#FO2017-0243), and a grant (#ALFGBG-715986) from the Swedish state under the agreement between the Swedish government and the County Councils, the ALF-agreement. NJA is supported by the Wallenberg Centre for Molecular and Translational Medicine, the Swedish Alzheimer Foundation (Alzheimerfonden), the Swedish Dementia Foundation (Demensförbundet), and Hjärnfonden, Sweden.

ObjectiveTo assess the diagnostic and prognostic value of serum neurofilament light (NfL) and serum phospho-Tau181(p-Tau181) in a large cohort of patients with frontotemporal lobar degeneration (FTLD).MethodsIn this retrospective study, performed on 417 participants, we analysed serum NfL and p-Tau181concentrations with an ultrasensitive single molecule array (Simoa) approach. We assessed the diagnostic values of serum biomarkers in the differential diagnosis between FTLD, Alzheimer’s disease (AD) and healthy ageing; their role as markers of disease severity assessing the correlation with clinical variables, cross-sectional brain imaging and neurophysiological data; their role as prognostic markers, considering their ability to predict survival probability in FTLD.ResultsWe observed significantly higher levels of serum NfL in patients with FTLD syndromes, compared with healthy controls, and lower levels of p-Tau181compared with patients with AD. Serum NfL concentrations showed a high accuracy in discriminating between FTLD and healthy controls (area under the curve (AUC): 0.86, p181showed high accuracy in differentiating FTLD from patients with AD (AUC: 0.93, pConclusionsThe assessment of serum NfL and p-Tau181may provide a comprehensive view of FTLD, aiding in the differential diagnosis, in staging disease severity and in defining survival probability.

The inter-cellular propagation of tau aggregates in several neurodegenerative diseases involves, in part, recurring cycles of extracellular tau uptake, initiation of endogenous tau aggregation, and extracellular release of at least part of this protein complex. However, human brain tau extracts from diverse tauopathies exhibit variant or “strain” specificity in inducing inter-cellular propagation in both cell and animal models. It is unclear if these distinctive properties are affected by disease-specific differences in aggregated tau conformation and structure. We have used a combined structural and cell biological approach to study if two frontotemporal dementia (FTD)-associated pathologic mutations, V337M and N279K, affect the aggregation, conformation and cellular internalization of the tau four-repeat domain (K18) fragment. In both heparin-induced and native-state aggregation experiments, each FTD variant formed soluble and fibrillar aggregates with remarkable morphological and immunological distinctions from the wild type (WT) aggregates. Exogenously applied oligomers of the FTD tau-K18 variants (V337M and N279K) were significantly more efficiently taken up by SH-SY5Y neuroblastoma cells than WT tau-K18, suggesting mutation-induced changes in cellular internalization. However, shared internalization mechanisms were observed: endocytosed oligomers were distributed in the cytoplasm and nucleus of SH-SY5Y cells and the neurites and soma of human induced pluripotent stem cell-derived neurons, where they co-localized with endogenous tau and the nuclear protein nucleolin. Altogether, evidence of conformational and aggregation differences between WT and disease-mutated tau K18 is demonstrated, which may explain their distinct cellular internalization potencies. These findings may account for critical aspects of the molecular pathogenesis of tauopathies involving WT and mutated tau.\ud \ud

Increasing evidence suggests that small oligomers are the principal neurotoxic species of tau in Alzheimer's disease and other tauopathies. However, mechanisms of tau oligomer-mediated neurodegeneration are poorly understood. The transience of oligomers due to aggregation can compromise the stability of oligomers prepared in vitro. Consequently, we sought to develop an efficient method which maintains the stability and globular conformation of preformed oligomers. This study demonstrates that labeling a single-cysteine form of the pro-aggregant tau four-repeat region (K18) with either Alexa Fluor 488-C5-maleimide or N-ethylmaleimide in reducing conditions stabilizes oligomers by impeding their further aggregation. Furthermore, the use of this approach to study the propagation of labeled extracellular tau K18 oligomers into human neuroblastoma cells and human stem cell-derived neurons is described. This method is potentially applicable for preparing stabilized oligomers of tau for diagnostic and biomarker tests, as well as for in vitro structure-activity relationship assays., Highlights • The transient nature of tau aggregation makes it difficult to maintain the stability of preformed oligomers. • Efficient labeling of tau K18 with Alexa Fluor-488-C5-maleimide or N-ethyl maleimide stabilizes the resulting oligomers. • Oligomers applied exogenously are propagated intracellularly by cultured human iPSC neurons and neuroblastoma cells. • Oligomer preparation by maleimide labeling allows mechanistic studies of tau aggregation and its link to neurodegeneration.

Comparable data on the global and country-specific burden of neurological disorders and their trends are crucial for health-care planning and resource allocation. The Global Burden of Diseases, Injuries, and Risk Factors (GBD) Study provides such information but does not routinely aggregate results that are of interest to clinicians specialising in neurological conditions. In this systematic analysis, we quantified the global disease burden due to neurological disorders in 2015 and its relationship with country development level.We estimated global and country-specific prevalence, mortality, disability-adjusted life-years (DALYs), years of life lost (YLLs), and years lived with disability (YLDs) for various neurological disorders that in the GBD classification have been previously spread across multiple disease groupings. The more inclusive grouping of neurological disorders included stroke, meningitis, encephalitis, tetanus, Alzheimer's disease and other dementias, Parkinson's disease, epilepsy, multiple sclerosis, motor neuron disease, migraine, tension-type headache, medication overuse headache, brain and nervous system cancers, and a residual category of other neurological disorders. We also analysed results based on the Socio-demographic Index (SDI), a compound measure of income per capita, education, and fertility, to identify patterns associated with development and how countries fare against expected outcomes relative to their level of development.Neurological disorders ranked as the leading cause group of DALYs in 2015 (250·7 [95% uncertainty interval (UI) 229·1 to 274·7] million, comprising 10·2% of global DALYs) and the second-leading cause group of deaths (9·4 [9·1 to 9·7] million], comprising 16·8% of global deaths). The most prevalent neurological disorders were tension-type headache (1505·9 [UI 1337·3 to 1681·6 million cases]), migraine (958·8 [872·1 to 1055·6] million), medication overuse headache (58·5 [50·8 to 67·4 million]), and Alzheimer's disease and other dementias (46·0 [40·2 to 52·7 million]). Between 1990 and 2015, the number of deaths from neurological disorders increased by 36·7%, and the number of DALYs by 7·4%. These increases occurred despite decreases in age-standardised rates of death and DALYs of 26·1% and 29·7%, respectively; stroke and communicable neurological disorders were responsible for most of these decreases. Communicable neurological disorders were the largest cause of DALYs in countries with low SDI. Stroke rates were highest at middle levels of SDI and lowest at the highest SDI. Most of the changes in DALY rates of neurological disorders with development were driven by changes in YLLs.Neurological disorders are an important cause of disability and death worldwide. Globally, the burden of neurological disorders has increased substantially over the past 25 years because of expanding population numbers and ageing, despite substantial decreases in mortality rates from stroke and communicable neurological disorders. The number of patients who will need care by clinicians with expertise in neurological conditions will continue to grow in coming decades. Policy makers and health-care providers should be aware of these trends to provide adequate services.BillMelinda Gates Foundation.

Ethnopharmacological Relevance. Mental and neurological disorders are a serious public health challenge globally, particularly in developing countries where cultural factors and limited access to standard healthcare have led to a reliance on traditional medicines. However, ethnopharmacological characterization of traditional medicines used to treat these diseases is lacking. In this study, an ethnobotanical description of plant species used in treating mental and neurological disorders in Ghana and an update of their experimentally validated pharmacological relevance are provided. Materials and Methods. Two hundred herbalists agreed to participate but sixty-six specialized in treating mental and neurological disorders were interviewed on their traditional medical practice. Literature review was conducted to verify the experimentally validated pharmacological importance of the reported plants. Results. Thirty-two plant species belonging to twenty-eight families were identified. Most plant species had either analgesic (50%), anxiolytic (18.8%), or anticonvulsant (15.6%) properties. Others had reported sedative, anti-Alzheimer’s disease, motor coordination, antipsychotic, antidepressant, cognitive enhancement, and neuroprotective properties. While Ageratum conyzoides L. (Asteraceae) and Ocimum gratissimum L. (Lamiaceae) were the most commonly mentioned species with analgesic properties, Lantana camara L. (Verbenaceae) was the most-reported anxiolytic product, with Cymbopogon citratus DC. (Gramineae), Mangifera indica L., Tetrapleura tetraptera Schum Taub. (Fabaceae), and Persea Americana Mill (Lauraceae) being the most studied anticonvulsants. Conclusions. This study provides the first report specifically on medicinal plants used in treating mental and neurological disorders in Ghana. Most of the identified plants have been scientifically confirmed to possess neuro- and psychopharmacological properties and may serve as templates for drug development.

Early involvement in public engagement activities may enhance undergraduate and graduate students’ long-term interest in science careers and their ability to dialogue with the public about topics of importance to science and society. While several public engagement training programs have been created and implemented in universities in the developed world, such opportunities are limited in developing countries. In their pursuit to develop appropriate public engagement training programs for their students, outreach providers and educators in developing countries will benefit from tried-and-tested training schemes from specific developing country contexts. In this paper, we describe the development, implementation, outcomes and possible extensions to an initiative to train budding scientists in a Ghanaian university to enable them to more effectively interact with the non-scientist public about the relevance of their research and the contribution of scientific endeavors to improving our daily lives. In order to address specific public engagement challenges identified in the target society, the program focuses on training students to become initiators of outreach activities who proactively seek engagement opportunities and can independently develop innovative events particularly for communities with poor public inclination to participate in scientific outreach.

While we are excited about the efforts of this journal to support scientific citizenship, we are concerned that science communication training efforts for budding scientists are lacking in many developing countries, casting doubts on measures to develop public engagement interest among the future scientific workforce in these environments. We discuss the need to address this challenge.

Neglected tropical diseases (NTDs) affect people in the bottom billion poorest in the world. These diseases are concentrated in rural areas, conflict zones and urban slums in Africa and other tropical areas. While the World Health Organization recognizes seventeen priority NTDs, the list of conditions present in Africa and elsewhere that are eligible to be classified as NTDs is much longer. Although NTDs are generally marginalized, their associated neurological burden has been almost completely disregarded. However, reports indicate that trichuriasis, schistosomiasis and hookworm infection, among others, cause impairments in memory and cognition, negatively affecting school attendance rates and educational performance particularly among children, as well as agricultural productivity among adults. Consequently, the neurological impairments have substantial influence on education and economic productivity, thus aggravating and perpetuating poverty in affected societies. However, inadequate research, policy and public health attention has been paid to the neurological burdens associated with NTDs. In order to appropriately address these burdens, we recommend the development of policy interventions that focus on the following areas: (i) the introduction of training programs to develop the capacity of scientists and clinicians in research, diagnostic and treatment approaches (ii) the establishment of competitive research grant schemes to fund cutting-edge research into these neurological impairments, and (iii) the development of public health interventions to improve community awareness of the NTD-associated neurological problems, possibly enhancing disease prevention and expediting treatment., Highlights • Neglected tropical diseases (NTDs) disproportionately affect the world’s poorest populations • While NTDs are generally marginalized, their associated neurological burden is almost completely disregarded in Africa • Neurological impairments of NTDs disrupt cognition and memory, thus adversely impacting education and health of affected families. • Policy interventions focused on advancing clinical research and early diagnosis and treatment paradigms are encouraged.

Modern genomic approaches have made enormous contributions to improving our understanding of the function, development and evolution of the nervous system, and the diversity within and between species. However, most of these research advances have been recorded in countries with advanced scientific resources and funding support systems. On the contrary, little is known about, for example, the possible interplay between different genes, non-coding elements and environmental factors in modulating neurological diseases among populations in low-income countries, including many African countries. The unique ancestry of African populations suggests that improved inclusion of these populations in neuroscience-related genomic studies would significantly help to identify novel factors that might shape the future of neuroscience research and neurological healthcare. This perspective is strongly supported by the recent identification that diseased individuals and their kindred from specific sub-Saharan African populations lack common neurological disease-associated genetic mutations. This indicates that there may be population-specific causes of neurological diseases, necessitating further investigations into the contribution of additional, presently-unknown genomic factors. Here, we discuss how the development of neurogenomics research in Africa would help to elucidate disease-related genomic variants, and also provide a good basis to develop more effective therapies. Furthermore, neurogenomics would harness African scientists' expertise in neuroscience, genomics and bioinformatics to extend our understanding of the neural basis of behaviour, development and evolution.

Research in bioinformatics has a central role in helping to advance biomedical research. However, its introduction to Africa has been met with some challenges (such as inadequate infrastructure, training opportunities, research funding, human resources, biorepositories and databases) that have contributed to the slow pace of development in this field across the continent. Fortunately, recent improvements in areas such as research funding, infrastructural support and capacity building are helping to develop bioinformatics into an important discipline in Africa. These contributions are leading to the establishment of world-class research facilities, biorepositories, training programmes, scientific networks and funding schemes to improve studies into disease and health in Africa. With increased contribution from all stakeholders, these developments could be further enhanced. Here, we discuss how the recent developments are contributing to the advancement of bioinformatics in Africa.

Background Underground water is an important natural resource serving as a reliable source of drinking water for many people worldwide, especially in developing countries. Underground water quality needs to be given a primary research and quality control attention due to possible contamination. This study was therefore designed to determine the physico-chemical and bacteriological quality of borehole water in the Upper West and Northern regions of Ghana. Methods The study was conducted in seven districts in Ghana (including six in the Upper West region and one in the Northern region). The bacterial load of the water samples was determined using standard microbiological methods. Physico-chemical properties including pH, total alkalinity, temperature, turbidity, true colour, total dissolved solids (TDS), electrical conductivity, total hardness, calcium hardness, magnesium hardness, total iron, calcium ion, magnesium ion, chloride ion, fluoride ion, aluminium ion, arsenic, ammonium ions, nitrate and nitrite concentrations were determined. The values obtained were compared with the World Health Organization (WHO) standards for drinking water. Results The recorded pH, total alkalinity and temperature ranges were 6.14–7.50, 48–240 mg/l and 28.8–32.8 °C, respectively. Furthermore, the mean concentrations of iron, calcium, magnesium, chloride, fluoride, aluminium, arsenic, ammonium, nitrate and nitrite were 0.06, 22.11, 29.84, 13.97, 0.00, 0.00, 0.00, 0.01, 2.09 and 0.26 mg/l, respectively. Turbidity, true colour, TDS and electrical conductivity of the water samples ranged from 0.13 to 105 NTU, 5 to 130 HU, 80.1 to 524 mg/l and 131 to 873 µS/cm, respectively. In addition, the mean total hardness value was found to be 178.07 mg/l whereas calcium hardness and magnesium hardness respectively were 55.28 and 122.79 mg/l. Only 14% of the water samples tested positive for faecal coliforms. Conclusion The study revealed that only a few of the values for the bacteriological and physico-chemical parameters of the water samples were above the tolerable limits recommended by the WHO. This calls for regular monitoring and purification of boreholes to ensure good water quality.

Background Integrity in academic work is a critical benchmark of every profession. For this reason, special attention should be devoted to addressing academic dishonesty (AD) in higher education to prevent the potential transfer of these practices to the workplace. In order to effectively address AD in Africa, further information about correlates of, and barriers to, the effectiveness of existing AD-controlling measures is needed. In Ghana, little is known about AD from the perspective of students. Here, we present a first report of Ghanaian undergraduate students’ self-reported understanding of, and support for, institutional AD regulations, their involvement in specific dishonest behaviours, as well as their motivation factors. Results Approximately 92 % of respondents said they were aware of institutional regulations on AD. However, only 31 % rated their understanding as high. Respondents believed that their lecturers had better understanding of, and support for, these regulations than the students (p