Abstract Background Proteins pathogenic in Alzheimer's disease (AD) were extracted from neurally derived blood exosomes and quantified to develop biomarkers for the staging of sporadic AD. Methods ...Blood exosomes obtained at one time-point from patients with AD (n = 57) or frontotemporal dementia (FTD) (n = 16), and at two time-points from others (n = 24) when cognitively normal and 1 to 10 years later when diagnosed with AD were enriched for neural sources by immunoabsorption. AD-pathogenic exosomal proteins were extracted and quantified by enzyme-linked immunosorbent assays. Results Mean exosomal levels of total tau, P-T181-tau, P-S396-tau, and amyloid β 1–42 (Aβ1–42) for AD and levels of P-T181-tau and Aβ1–42 for FTD were significantly higher than for case-controls. Step-wise discriminant modeling incorporated P-T181-tau, P-S396-tau, and Aβ1–42 in AD, but only P-T181-tau in FTD. Classification of 96.4% of AD patients and 87.5% of FTD patients was correct. In 24 AD patients, exosomal levels of P-S396-tau, P-T181-tau, and Aβ1–42 were significantly higher than for controls both 1 to 10 years before and when diagnosed with AD. Conclusions Levels of P-S396-tau, P-T181-tau, and Aβ1–42 in extracts of neurally derived blood exosomes predict the development of AD up to 10 years before clinical onset.
The increasing number of afflicted individuals with late-onset Alzheimer's disease (AD) poses significant emotional and financial burden on the world's population. Therapeutics designed to treat ...symptoms or alter the disease course have failed to make an impact, despite substantial investments by governments, pharmaceutical industry, and private donors. These failures in treatment efficacy have led many to believe that symptomatic disease, including both mild cognitive impairment (MCI) and AD, may be refractory to therapeutic intervention. The recent focus on biomarkers for defining the preclinical state of MCI/AD is in the hope of defining a therapeutic window in which the neural substrate remains responsive to treatment. The ability of biomarkers to adequately define the at-risk state may ultimately allow novel or repurposed therapeutic agents to finally achieve the disease-modifying status for AD. In this review, we examine current preclinical AD biomarkers and suggest how to generalize their use going forward.
Summary Background Accurate diagnosis and early detection of complex diseases, such as Parkinson's disease, has the potential to be of great benefit for researchers and clinical practice. We aimed to ...create a non-invasive, accurate classification model for the diagnosis of Parkinson's disease, which could serve as a basis for future disease prediction studies in longitudinal cohorts. Methods We developed a model for disease classification using data from the Parkinson's Progression Marker Initiative (PPMI) study for 367 patients with Parkinson's disease and phenotypically typical imaging data and 165 controls without neurological disease. Olfactory function, genetic risk, family history of Parkinson's disease, age, and gender were algorithmically selected by stepwise logistic regression as significant contributors to our classifying model. We then tested the model with data from 825 patients with Parkinson's disease and 261 controls from five independent cohorts with varying recruitment strategies and designs: the Parkinson's Disease Biomarkers Program (PDBP), the Parkinson's Associated Risk Study (PARS), 23andMe, the Longitudinal and Biomarker Study in PD (LABS-PD), and the Morris K Udall Parkinson's Disease Research Center of Excellence cohort (Penn-Udall). Additionally, we used our model to investigate patients who had imaging scans without evidence of dopaminergic deficit (SWEDD). Findings In the population from PPMI, our initial model correctly distinguished patients with Parkinson's disease from controls at an area under the curve (AUC) of 0·923 (95% CI 0·900–0·946) with high sensitivity (0·834, 95% CI 0·711–0·883) and specificity (0·903, 95% CI 0·824–0·946) at its optimum AUC threshold (0·655). All Hosmer-Lemeshow simulations suggested that when parsed into random subgroups, the subgroup data matched that of the overall cohort. External validation showed good classification of Parkinson's disease, with AUCs of 0·894 (95% CI 0·867–0·921) in the PDBP cohort, 0·998 (0·992–1·000) in PARS, 0·955 (no 95% CI available) in 23andMe, 0·929 (0·896–0·962) in LABS-PD, and 0·939 (0·891–0·986) in the Penn-Udall cohort. Four of 17 SWEDD participants who our model classified as having Parkinson's disease converted to Parkinson's disease within 1 year, whereas only one of 38 SWEDD participants who were not classified as having Parkinson's disease underwent conversion (test of proportions, p=0·003). Interpretation Our model provides a potential new approach to distinguish participants with Parkinson's disease from controls. If the model can also identify individuals with prodromal or preclinical Parkinson's disease in prospective cohorts, it could facilitate identification of biomarkers and interventions. Funding National Institute on Aging, National Institute of Neurological Disorders and Stroke, and the Michael J Fox Foundation.
Background
People with Down syndrome (DS) are at high risk for Alzheimer’s disease (AD) in part because nearly all carry an extra copy of the APP gene which results in overexpression of amyloid. ...However, other factors are likely to interact with this genetic risk to produce individual pathobiological and clinical trajectories. We sought to examine the impact of diverse physiological pathways on AD risk in people with DS using plasma metabolomics.
Method
We studied the plasma metabolome of 744 people with DS (mean age =49) using mass spectrometry (MS). A total of 144 individuals from our cohort met criteria for MCI or AD (DS‐AD, mean age= 55.0) and 600 were cognitively stable (DS‐NAD, mean age = 47.4). We quantified the relative abundance of over 7000 putative metabolites. We performed differential expression (DE) analysis and constructed group classification models (DS‐AD vs DS‐NAD) using Regularized Logistic Regression with age included as a covariate. We evaluated the classification models using Receiver Operating Characteristic (ROC) analysis.
Result
We found 20 DE features between the DS‐AD and DS‐NAD groups (q < 0.05), of which we definitively identified 11 through tandem mass spectrometry. Of the 11 metabolites, 5 were naturally occurring unique human metabolites involved in fatty acid metabolism, including two diacylglycerides, one monoglyceride, one lysophosphatidycholine, and one acylcarnitine. When combined, this set of lipids classified the DS‐AD and DS‐NAD groups with ROC area under the curve of 0.796 95% CI: 0.784‐ 0.808 across resamples (Sensitivity 29%, Specificity 97%). The addition of participant sex or APOE status did not significantly alter classification performance.
Conclusion
Here, we find depletion of lipids in the plasma of people with DS who also have AD compared to people with DS who are not demented. While the overall number of DE metabolites is small, it is remarkable that from over 7000 putative metabolites measured, all are lipids involved in fatty acid metabolism. These results are consistent with an emerging picture of dysregulated lipid metabolism in AD, both in the people with DS and in the neurotypical population.
Recent reports implicate gut microbiome dysbiosis in the onset and progression of Alzheimer's disease (AD), yet studies involving model animals overwhelmingly omit the microbial perspective. Here, we ...evaluate longitudinal microbiomes and metabolomes from a popular transgenic mouse model for familial AD (5xfAD). Cecal and fecal samples from 5xfAD and wild-type B6J (WT) mice from 4 to 18 months of age were subjected to shotgun Illumina sequencing. Metabolomics was performed on plasma and feces from a subset of the same animals. Significant genotype, sex, age, and cage-specific differences were observed in the microbiome, with the variance explained by genotype at 4 and 18 months of age rising from 0.9 to 9% and 0.3 to 8% for the cecal and fecal samples, respectively. Bacteria at significantly higher abundances in AD mice include multiple
spp., two
spp., and
sp. P38, while multiple species of
, Lactobacillus johnsonii, and Romboutsia ilealis were less abundant.
is similarly depleted in people with AD, and members of this genus both consume and induce the production of gut-derived serotonin. Contradicting previous findings in humans, serotonin is significantly more concentrated in the blood of older 5xfAD animals compared to their WT littermates. 5xfAD animals exhibited significantly lower plasma concentrations of carnosine and the lysophospholipid lysoPC a C18:1. Correlations between the microbiome and metabolome were also explored. Taken together, these findings strengthen the link between
abundance and AD, provide a basis for further microbiome studies of murine models for AD, and suggest that greater control over animal model microbiomes is needed in AD research.
Microorganisms residing within the gastrointestinal tract are implicated in the onset and progression of Alzheimer's disease (AD) through the mediation of inflammation, exchange of small-molecules across the blood-brain barrier, and stimulation of the vagus nerve. Unfortunately, most animal models for AD are housed under conditions that do not reflect real-world human microbial exposure and do not sufficiently account for (or meaningfully consider) variations in the microbiome. An improved understanding of AD model animal microbiomes will increase model efficacy and the translatability of research findings into humans. Here, we present the characterization of the microbiome and metabolome of the 5xfAD mouse model, which is one of the most common animal models for familial AD. The manuscript highlights the importance of considering the microbiome in study design and aims to lay the groundwork for future studies involving mouse models for AD.
Past and recent attempts at devising objective biomarkers for traumatic brain injury (TBI) in both blood and cerebrospinal fluid have focused on abundance measures of time-dependent proteins. Similar ...independent determinants would be most welcome in diagnosing the most common form of TBI, mild TBI (mTBI), which remains difficult to define and confirm based solely on clinical criteria. There are currently no consensus diagnostic measures that objectively define individuals as having sustained an acute mTBI. Plasma metabolomic analyses have recently evolved to offer an alternative to proteomic analyses, offering an orthogonal diagnostic measure to what is currently available. The purpose of this study was to determine whether a developed set of metabolomic biomarkers is able to objectively classify college athletes sustaining mTBI from non-injured teammates, within 6 hours of trauma and whether such a biomarker panel could be effectively applied to an independent cohort of TBI and control subjects. A 6-metabolite panel was developed from biomarkers that had their identities confirmed using tandem mass spectrometry (MS/MS) in our Athlete cohort. These biomarkers were defined at ≤6 hours following mTBI and objectively classified mTBI athletes from teammate controls, and provided similar classification of these groups at the 2, 3, and 7 days post-mTBI. The same 6-metabolite panel, when applied to a separate, independent cohort provided statistically similar results despite major differences between the two cohorts. Our confirmed plasma biomarker panel objectively classifies acute mTBI cases from controls within 6 hours of injury in our two independent cohorts. While encouraged by our initial results, we expect future studies to expand on these initial observations.
Our study aimed to investigate the short-term effect of combination antiretroviral therapy (cART) on cognitive performance and functional and structural connectivity and their relationship to plasma ...levels of antiretroviral (ARV) drugs. Seventeen ARV treatment-naïve HIV-infected individuals (baseline mean CD4 cell count, 479 ± 48 cells/mm
3
) were age matched with 17 HIV-uninfected individuals. All subjects underwent a detailed neurocognitive and functional assessment and magnetic resonance imaging. HIV-infected subjects were scanned before starting cART and 12 weeks after initiation of treatment. Uninfected subjects were assessed once at baseline. Functional connectivity (FC) was assessed within the default mode network while structural connectivity was assessed by voxel-wise analysis using tract-based spatial statistics (TBSS) and probabilistic tractography within the DMN. Tenofovir and emtricitabine blood concentration were measured at week 12 of cART. Prior to cART, HIV-infected individuals had significantly lower cognitive performance than control subjects as measured by the total Z-score from the neuropsychological tests assessing six cognitive domains (
p
= 0.020). After 12 weeks of cART treatment, there remained only a weak cognitive difference between HIV-infected and HIV-uninfected subjects (
p
= 0.057). Mean FC was lower in HIV-infected individuals compared with those uninfected (
p
= 0.008), but FC differences became non-significant after treatment (
p
= 0.197). There were no differences in DTI metrics between HIV-infected and HIV-uninfected individuals using the TBSS approach and limited evidence of decreased structural connectivity within the DMN in HIV-infected individuals. Tenofovir and emtricitabine plasma concentrations did not correlate with either cognitive performance or imaging metrics. Conclusions: Twelve weeks of cART improves cognitive performance and functional connectivity in ARV treatment-naïve HIV-infected individuals with relatively preserved immune function. Longer periods of observation are necessary to assess whether this effect is maintained.
Adults with Down syndrome have a genetic form of Alzheimer's disease (AD) and evidence of cerebrovascular disease across the AD continuum, despite few systemic vascular risk factors. The onset and ...progression of AD in Down syndrome is highly age-dependent, but it is unknown at what age cerebrovascular disease emerges and what factors influence its severity. In the Alzheimer's Biomarker Consortium-Down Syndrome study (ABC-DS; n = 242; age = 25-72), we estimated the age inflection point at which MRI-based white matter hyperintensities (WMH), enlarged perivascular spaces (PVS), microbleeds, and infarcts emerge in relation to demographic data, risk factors, amyloid and tau, and AD diagnosis. Enlarged PVS and infarcts appear to develop in the early 30s, while microbleeds, WMH, amyloid, and tau emerge in the mid to late 30s. Age-residualized WMH were higher in women, in individuals with dementia, and with lower body mass index. Participants with hypertension and APOE-ε4 had higher age-residualized PVS and microbleeds, respectively. Lifespan trajectories demonstrate a dramatic cerebrovascular profile in adults with Down syndrome that appears to evolve developmentally in parallel with AD pathophysiology approximately two decades prior to dementia symptoms.
Pancreatic cancer (PC) is an aggressive disease with high mortality rates, however, there is no blood test for early detection and diagnosis of this disease. Several research groups have reported on ...metabolomics based clinical investigations to identify biomarkers of PC, however there is a lack of a centralized metabolite biomarker repository that can be used for meta-analysis and biomarker validation. Furthermore, since the incidence of PC is associated with metabolic syndrome and Type 2 diabetes mellitus (T2DM), there is a need to uncouple these common metabolic dysregulations that may otherwise diminish the clinical utility of metabolomic biosignatures. Here, we attempted to externally replicate proposed metabolite biomarkers of PC reported by several other groups in an independent group of PC subjects. Our study design included a T2DM cohort that was used as a non-cancer control and a separate cohort diagnosed with colorectal cancer (CRC), as a cancer disease control to eliminate possible generic biomarkers of cancer. We used targeted mass spectrometry for quantitation of literature-curated metabolite markers and identified a biomarker panel that discriminates between normal controls (NC) and PC patients with high accuracy. Further evaluation of our model with CRC, however, showed a drop in specificity for the PC biomarker panel. Taken together, our study underscores the need for a more robust study design for cancer biomarker studies so as to maximize the translational value and clinical implementation.
PDF
