Citations

Abstract Genetic frontotemporal lobar degeneration caused by autosomal dominant gene mutations provides an opportunity for targeted drug development in a highly complex and clinically heterogeneous dementia. These neurodegenerative disorders can affect adults in their middle years, progress quickly relative to other dementias, are uniformly fatal and have no approved disease-modifying treatments. Frontotemporal dementia, caused by mutations in the GRN gene which encodes the protein progranulin, is an active area of interventional drug trials that are testing multiple strategies to restore progranulin protein deficiency. These and other trials are also examining neurofilament light as a potential biomarker of disease activity and disease progression and as a therapeutic endpoint based on the assumption that cerebrospinal fluid and blood neurofilament light levels are a surrogate for neuroaxonal damage. Reports from genetic frontotemporal dementia longitudinal studies indicate that elevated concentrations of blood neurofilament light reflect disease severity and are associated with faster brain atrophy. To better inform patient stratification and treatment response in current and upcoming clinical trials, a more nuanced interpretation of neurofilament light as a biomarker of neurodegeneration is now required, one that takes into account its relationship to other pathophysiological and topographic biomarkers of disease progression from early presymptomatic to later clinically symptomatic stages.

Abstract Extracellular vesicles have emerged as a less-invasive nano-tool for discovering biomarkers of Alzheimer’s disease and related dementia. Here, we analysed different neuron-enriched extracellular vesicles from plasma to predict response and molecular mechanisms of ketogenic diet’s efficacy in mild cognitive impairment participants. The study was a randomized crossover design in which cognitively normal and mild cognitive impairment participants consumed a modified Mediterranean-ketogenic diet or American Heart Association diet for 6 weeks, followed by other diet after washout. L1 cell adhesion molecule, synaptophysin and neural cell adhesion molecule surface markers were used to enrich for neuron-secreted small extracellular vesicles (sEVL1CAM, sEVSYP and sEVNCAM). For the first time, we have presented multiple evidences, including immunogold labelling/transmission electron microscopy, clusters of differentiation 63-ELISA-based assay, confocal microscopy fluorescent images and flow cytometry data confirming the presence of L1 cell adhesion molecule on the surface of sEVL1CAM, validating purity and relative abundance of sEVL1CAM in the plasma. Cargo analysis of sEVL1CAM showed that modified Mediterranean-ketogenic diet intervention reduces amyloid beta 1–42 (50.3%, P = 0.011), p181-tau (34.9%, P = 0.033) and neurofilament light (54.2%, P = 0.020) in mild cognitive impairment participants. Moreover, sEVL1CAMshowed better sensitivity compared with CSF in analysing increased glutamate (6-folds, P < 0.0001) from mild cognitive impairment participants following modified Mediterranean-ketogenic diet intervention. sEVL1CAM characterization also suggested that modified Mediterranean-ketogenic diet differentially targets the expression of various glutamate receptors—glutamate receptor ionotropic NMDA1, glutamate receptor ionotropic NMDA2A, glutamate receptor ionotropic NMDA2B and glutamate receptor ionotropic AMPA type subunit 1. Importantly, these sEVL1CAM measures strongly correlated with corresponding clinical CSF biomarkers (neurogranin, amyloid beta 1–42, neurofilament light and tau). Furthermore, sEVL1CAM were loaded with less advanced glycation endproducts and exhibited anti-inflammatory activity following modified Mediterranean-ketogenic diet intervention. Most importantly, the expression of monocarboxylate transporter 2 on the surface of sEVL1CAM predicted the amyloid beta 1–42 response to modified Mediterranean-ketogenic diet intervention (area under the curve = 0.87, P = 0.0044) and offered a novel screening tool to identify participants responsive to this dietary intervention. Finally, sEVL1CAM, sEVSYP and sEVNCAM showed significantly high concordance in analysing amyloid beta 1–42 (Pearson correlation coefficient ≥ 0.63, P < 0.01) and neurofilament light (Pearson correlation coefficient ≥ 0.49, P < 0.05). Together, small extracellular vesicles in plasma offers promise in assessing the efficacy of dietary/therapeutic intervention against mild cognitive impairment/Alzheimer’s disease.

AbstractBackground and purposeClinical trials in spinocerebellar ataxia type 3 (SCA3) will require biomarkers for use as outcome measures.MethodsTo evaluate total tau (t‐tau), glial fibrillary acidic protein (GFAP), ubiquitin carboxy‐terminal hydrolase L1 (UCHL1) and neurofilament light‐chain (NfL) as fluid biomarkers in SCA3, ATXN3 mutation carriers (n = 143) and controls (n = 172) were clinically assessed, and the plasma concentrations of the four proteins were analysed on the Simoa HD‐1 platform. Eleven ATXN3 mutation carrier cerebrospinal fluid samples were analysed for t‐tau and phosphorylated tau (p‐tau181). A transgenic SCA3 mouse model (MJDTg) was used to measure cerebellar t‐tau levels.ResultsPlasma t‐tau levels were higher in mutation carriers below the age of 50 compared to controls, and the Inventory of Non‐Ataxia Signs was associated with t‐tau in ataxic patients (p = 0.004). Pre‐ataxic carriers showed higher cerebrospinal fluid t‐tau and p‐tau181 concentrations compared to ataxic patients (p = 0.025 and p = 0.014, respectively). Cerebellar t‐tau was elevated in MJDTg mice compared to wild‐type (p = 0.033) only in the early stages of the disease. GFAP and UCHL1 did not show higher levels in mutation carriers compared to controls. Plasma NfL concentrations were higher in mutation carriers compared to controls, and differences were greater for younger carriers. The Scale for the Assessment and Rating of Ataxia was the strongest predictor of NfL in ataxic patients (p < 0.001).ConclusionOur results suggest that tau might be a marker of early disease stages in SCA3. NfL can discriminate mutation carriers from controls and is associated with different clinical variables. Longitudinal studies are required to confirm their potential role as biomarkers in clinical trials.

Abstract Preclinical Alzheimer’s disease describes some individuals who harbour Alzheimer’s pathologies but are asymptomatic. For this study, we hypothesized that genetic variation may help protect some individuals from Alzheimer’s-related neurodegeneration. We therefore conducted a genome-wide association study using 5 891 064 common variants to assess whether genetic variation modifies the association between baseline beta-amyloid, as measured by both cerebrospinal fluid and positron emission tomography, and neurodegeneration defined using MRI measures of hippocampal volume. We combined and jointly analysed genotype, biomarker and neuroimaging data from non-Hispanic white individuals who were enrolled in four longitudinal ageing studies (n = 1065). Using regression models, we examined the interaction between common genetic variants (Minor Allele Frequency &gt;0.01), including APOE-ɛ4 and APOE-ɛ2, and baseline cerebrospinal levels of amyloid (CSF Aβ42) on baseline hippocampal volume and the longitudinal rate of hippocampal atrophy. For targeted replication of top findings, we analysed an independent dataset (n = 808) where amyloid burden was assessed by Pittsburgh Compound B ([11C]-PiB) positron emission tomography. In this study, we found that APOE-ɛ4 modified the association between baseline CSF Aβ42 and hippocampal volume such that APOE-ɛ4 carriers showed more rapid atrophy, particularly in the presence of enhanced amyloidosis. We also identified a novel locus on chromosome 3 that interacted with baseline CSF Aβ42. Minor allele carriers of rs62263260, an expression quantitative trait locus for the SEMA5B gene (P = 1.46 × 10−8; 3:122675327) had more rapid neurodegeneration when amyloid burden was high and slower neurodegeneration when amyloid was low. The rs62263260 × amyloid interaction on longitudinal change in hippocampal volume was replicated in an independent dataset (P = 0.0112) where amyloid burden was assessed by positron emission tomography. In addition to supporting the established interaction between APOE and amyloid on neurodegeneration, our study identifies a novel locus that modifies the association between beta-amyloid and hippocampal atrophy. Annotation results may implicate SEMA5B, a gene involved in synaptic pruning and axonal guidance, as a high-quality candidate for functional confirmation and future mechanistic analysis.

Abstract Introduction In this longitudinal study, we aimed to examine if slowing gait speed preceded cognitive decline and correlated with brain amyloidosis. Methods The sample (n = 287) was derived from the Gothenburg H70 Birth Cohort Studies, with follow‐ups between 2000 and 2015. Gait speed was measured by indoor walk, and cognition using the Clinical Dementia Rating (CDR) score. All participants had CDR = 0 at baseline. Some participants had data on cerebrospinal fluid (CSF) amyloid beta (Aβ) 1‐42 concentrations at the 2009 examination. Results Gait speed for participants who worsened in CDR score during follow‐up was slower at most examinations. Baseline gait speed could significantly predict CDR change from baseline to follow‐up. Subjects with pathological CSF Aβ 1‐ 42 concentrations at the 2009 visit had lost more gait speed compared to previous examinations. Discussion Our results indicate that gait speed decline precedes cognitive decline, is linked to Alzheimer's pathology, and might be used for early detection of increased risk for dementia development.

AbstractBackgroundAPOE4 gene dose, the number of apolipoprotein E ‐ɛ4 (APOE4) ɛ4 alleles in a person’s genotype, is associated with higher Alzheimer’s disease (AD) risk and younger median age at dementia onset. We previously found relationships between PET, plasma, and CSF measurements of amyloid‐β (Aβ) pathophysiology in APOE4 gene dose. Here, we characterize the core AD CSF biomarkers (Aβ42/40, pTau181, tTau), the neurodegeneration marker neurofilament light chain (NfL) and the glial biomarkers soluble TREM2 (sTREM2), and glial fibrillary acidic protein (GFAP) measurements in age‐matched 48‐70 year‐old cognitively unimpaired (CU) APOE4 homozygotes (HMs), heterozygotes (HTs) and non‐carriers (NCs) from the Arizona cohort.MethodCSF biomarker measurements were performed at the University of Gothenburg using Lumipulse and ELISA immunoassays. CSF biomarker measurements were characterized and compared using linear‐tend ANOVAs in 12 HMs, 17 HTs, and 20 NCs who were CU, 48‐70 years old and did not differ significantly in their age, sex, or educational level.ResultAs expected, CSF Aβ42/40 ratios were inversely associated with APOE4 gene dose (linear trend, HM<HT<NC, p<0.05), and tTau/Aβ42 and pTau181/Aβ42 ratios were directly associated with APOE4 gene dose (HM>HT>NC p<0.05). Non‐significant trends suggested that CSF sTREM2 and sTREM2/pTau181 measurements were inversely associated with APOE4 gene dose (HM<HT≤NC, (0.05<p≤0.06). We failed to detect significant differences or linear trends in CSF pTau181, tTau, GFAP, or NfL measurements among these small subject groups.ConclusionAPOE4 gene dose is associated with measures of CSF Aβ42/40 and Aβ‐related tau pathophysiology, reflecting higher Aβ plaque burden in CU subjects close to their estimated ages at clinical onset. Additional studies are needed to clarify relationships between different Aβ, tau, neurodegenerative, inflammatory, and other CSF, or blood‐based biomarkers, and APOE4 gene dose in larger subject groups and at other ages.

AbstractBackgroundBlood phosphorylated tau (p‐tau) has proven to be the primary candidate as an accessible and scalable biomarker for Alzheimer’s disease (AD). Both p‐tau181 and p‐tau217 are highly accurate to detect AD within dementia cases. Our recent work in cerebrospinal fluid, however, indicates p‐tau231 to be associated to incipient AD pathology. In light of this, we developed a Single molecule array (Simoa) to detect plasma p‐tau231 and assessed its performance in multiple domains, specifically, its ability to detect preclinical AD.MethodIn all cohorts, plasma p‐tau231 was quantified using an in‐house Simoa method developed at the Clinical Neurochemistry Laboratory, Gothenburg University, Sweden. Data presented in this study are samples acquired from Translational Biomarkers of Aging and Dementia (TRIAD, n=503), King’s College London (n=55), Mayo Clinic Study of Aging (n=145), KARVIAH (n=140), Baltimore Longitudinal Study of Aging (n=430), University College London (n=70), Paris University (n=213), PREVENT‐AD (n=257), University of California (n=309) and ALFA+ (n=385).ResultIn the TRIAD cohort, plasma p‐tau231 demonstrated high accuracy in determining AD from young individuals (AUC=0.95), Aβ‐ elderly (AUC=0.92), Aβ‐ MCI (AUC=0.88) and other neurodegenerative disorders (AUC=0.92). In an autopsy study, plasma p‐tau231 could detect neuropathologically confirmed AD amongst dementia cases (AUC=0.99). In comparing healthy elderly Aβ‐ and Aβ+ individuals, p‐tau231 predicted preclinical Aβ pathology (AUC=0.83). Furthermore, inflection points of the weighted regression curves demonstrate that increases in plasma p‐tau231 occur before plasma p‐tau181 as a function of Aβ deposition load. Plasma p‐tau231 data from additional cohorts will focus on cross‐sectional and longitudinal preclinical datasets. In addition, further data will show the performance of p‐tau231 in symptomatic and presymptomatic PSEN1/APP mutation carriers, memory clinic cohorts, longitudinal neuropathology confirmed and acute neurological injury.ConclusionPlasma p‐tau231 is a new biomarker specific for AD pathology and at higher concentrations relative to p‐tau181 and p‐tau217. Our initial results indicate that plasma p‐tau231 is equivalent to p‐tau181 in diagnostic utility but has greater potential as a biomarker to monitor emerging Aβ pathology. This presentation will give an overview of novel cross‐sectional and longitudinal plasma p‐tau231 data, in more than 3000 individuals, that encompasses the AD continuum, familial AD and other neurological conditions.

Abstract Introduction As cerebrospinal fluid (CSF) neurofilament light protein (NfL) and the CSF/serum albumin ratio (Q Alb ) are used in the clinical routine, the impact of demographic factors on these biomarkers is important to understand. Methods Participants were derived from two Swedish samples: the population‐based H70 Study (n = 308, age 70) and a clinical routine cohort (CSF NfL, n = 8995, Q Alb , n = 39252, age 0 to 95). In the population‐based study, Q Alb and NfL were examined in relation to sex, cardiovascular risk factors, and cerebral white matter lesions (WMLs). In the clinical cohort, Q Alb and NfL sex differences were tested in relation to age. Results Men had higher Q Alb and NfL concentrations and had higher Q Alb and NfL concentrations from adolescence throughout life. NfL was not related to WML, but Q Alb correlated positively with WMLs. Discussion The CSF NfL sex difference could not be explained by vascular pathology. Future studies should consider using different reference limits for men and women.