Showing papers by "John Q. Trojanowski published in 2017"

Diagnosis and management of dementia with Lewy bodies Fourth consensus report of the DLB Consortium

Abstract: The Dementia with Lewy Bodies (DLB) Consortium has refined its recommendations about the clinical and pathologic diagnosis of DLB, updating the previous report, which has been in widespread use for the last decade. The revised DLB consensus criteria now distinguish clearly between clinical features and diagnostic biomarkers, and give guidance about optimal methods to establish and interpret these. Substantial new information has been incorporated about previously reported aspects of DLB, with increased diagnostic weighting given to REM sleep behavior disorder and 123iodine-metaiodobenzylguanidine (MIBG) myocardial scintigraphy. The diagnostic role of other neuroimaging, electrophysiologic, and laboratory investigations is also described. Minor modifications to pathologic methods and criteria are recommended to take account of Alzheimer disease neuropathologic change, to add previously omitted Lewy-related pathology categories, and to include assessments for substantia nigra neuronal loss. Recommendations about clinical management are largely based upon expert opinion since randomized controlled trials in DLB are few. Substantial progress has been made since the previous report in the detection and recognition of DLB as a common and important clinical disorder. During that period it has been incorporated into DSM-5, as major neurocognitive disorder with Lewy bodies. There remains a pressing need to understand the underlying neurobiology and pathophysiology of DLB, to develop and deliver clinical trials with both symptomatic and disease-modifying agents, and to help patients and carers worldwide to inform themselves about the disease, its prognosis, best available treatments, ongoing research, and how to get adequate support.

Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease

Abstract: We identified rare coding variants associated with Alzheimer's disease in a three-stage case–control study of 85,133 subjects. In stage 1, we genotyped 34,174 samples using a whole-exome microarray. In stage 2, we tested associated variants (P < 1 × 10−4) in 35,962 independent samples using de novo genotyping and imputed genotypes. In stage 3, we used an additional 14,997 samples to test the most significant stage 2 associations (P < 5 × 10−8) using imputed genotypes. We observed three new genome-wide significant nonsynonymous variants associated with Alzheimer's disease: a protective variant in PLCG2 (rs72824905: p.Pro522Arg, P = 5.38 × 10−10, odds ratio (OR) = 0.68, minor allele frequency (MAF)cases = 0.0059, MAFcontrols = 0.0093), a risk variant in ABI3 (rs616338: p.Ser209Phe, P = 4.56 × 10−10, OR = 1.43, MAFcases = 0.011, MAFcontrols = 0.008), and a new genome-wide significant variant in TREM2 (rs143332484: p.Arg62His, P = 1.55 × 10−14, OR = 1.67, MAFcases = 0.0143, MAFcontrols = 0.0089), a known susceptibility gene for Alzheimer's disease. These protein-altering changes are in genes highly expressed in microglia and highlight an immune-related protein–protein interaction network enriched for previously identified risk genes in Alzheimer's disease. These genetic findings provide additional evidence that the microglia-mediated innate immune response contributes directly to the development of Alzheimer's disease.

Neuropathological and Genetic Correlates of Survival and Dementia Onset in Synucleinopathies: A Retrospective Analysis

Abstract: Summary Background Great heterogeneity exists in survival and the interval between onset of motor symptoms and dementia symptoms across synucleinopathies. We aimed to identify genetic and pathological markers that have the strongest association with these features of clinical heterogeneity in synucleinopathies. Methods In this retrospective study, we examined symptom onset, and genetic and neuropathological data from a cohort of patients with Lewy body disorders with autopsy-confirmed α synucleinopathy (as of Oct 1, 2015) who were previously included in other studies from five academic institutions in five cities in the USA. We used histopathology techniques and markers to assess the burden of tau neurofibrillary tangles, neuritic plaques, α-synuclein inclusions, and other pathological changes in cortical regions. These samples were graded on an ordinal scale and genotyped for variants associated with synucleinopathies. We assessed the interval from onset of motor symptoms to onset of dementia, and overall survival in groups with varying levels of comorbid Alzheimer's disease pathology according to US National Institute on Aging–Alzheimer's Association neuropathological criteria, and used multivariate regression to control for age at death and sex. Findings On the basis of data from 213 patients who had been followed up to autopsy and met inclusion criteria of Lewy body disorder with autopsy-confirmed α synucleinopathy, we identified 49 (23%) patients with no Alzheimer's disease neuropathology, 56 (26%) with low-level Alzheimer's disease neuropathology, 45 (21%) with intermediate-level Alzheimer's disease neuropathology, and 63 (30%) with high-level Alzheimer's disease neuropathology. As levels of Alzheimer's disease neuropathology increased, cerebral α-synuclein scores were higher, and the interval between onset of motor and dementia symptoms and disease duration was shorter (p 2 0·22, p MAPT haplotype, and APOE genotype as covariates. Interpretation Alzheimer's disease neuropathology is common in synucleinopathies and confers a worse prognosis for each increasing level of neuropathological change. Cerebral neurofibrillary tangles burden, in addition to α-synuclein pathology and amyloid plaque pathology, are the strongest pathological predictors of a shorter interval between onset of motor and dementia symptoms and survival. Diagnostic criteria based on reliable biomarkers for Alzheimer's disease neuropathology in synucleinopathies should help to identify the most appropriate patients for clinical trials of emerging therapies targeting tau, amyloid-β or α synuclein, and to stratify them by level of Alzheimer's disease neuropathology. Funding US National Institutes of Health (National Institute on Aging and National Institute of Neurological Disorders and Stroke).

Metabolic network failures in Alzheimer's disease: A biochemical road map

Abstract: Introduction The Alzheimer's Disease Research Summits of 2012 and 2015 incorporated experts from academia, industry, and nonprofit organizations to develop new research directions to transform our understanding of Alzheimer's disease (AD) and propel the development of critically needed therapies. In response to their recommendations, big data at multiple levels are being generated and integrated to study network failures in disease. We used metabolomics as a global biochemical approach to identify peripheral metabolic changes in AD patients and correlate them to cerebrospinal fluid pathology markers, imaging features, and cognitive performance. Methods Fasting serum samples from the Alzheimer's Disease Neuroimaging Initiative (199 control, 356 mild cognitive impairment, and 175 AD participants) were analyzed using the AbsoluteIDQ-p180 kit. Performance was validated in blinded replicates, and values were medication adjusted. Results Multivariable-adjusted analyses showed that sphingomyelins and ether-containing phosphatidylcholines were altered in preclinical biomarker-defined AD stages, whereas acylcarnitines and several amines, including the branched-chain amino acid valine and α-aminoadipic acid, changed in symptomatic stages. Several of the analytes showed consistent associations in the Rotterdam, Erasmus Rucphen Family, and Indiana Memory and Aging Studies. Partial correlation networks constructed for Aβ 1–42 , tau, imaging, and cognitive changes provided initial biochemical insights for disease-related processes. Coexpression networks interconnected key metabolic effectors of disease. Discussion Metabolomics identified key disease-related metabolic changes and disease-progression-related changes. Defining metabolic changes during AD disease trajectory and its relationship to clinical phenotypes provides a powerful roadmap for drug and biomarker discovery.

Typical and atypical pathology in primary progressive aphasia variants.

Abstract: Objective To characterize in vivo signatures of pathological diagnosis in a large cohort of patients with primary progressive aphasia (PPA) variants defined by current diagnostic classification. Methods Extensive clinical, cognitive, neuroimaging, and neuropathological data were collected from 69 patients with sporadic PPA, divided into 29 semantic (svPPA), 25 nonfluent (nfvPPA), 11 logopenic (lvPPA), and 4 mixed PPA. Patterns of gray matter (GM) and white matter (WM) atrophy at presentation were assessed and tested as predictors of pathological diagnosis using support vector machine (SVM) algorithms. Results A clinical diagnosis of PPA was associated with frontotemporal lobar degeneration (FTLD) with transactive response DNA-binding protein (TDP) inclusions in 40.5%, FTLD-tau in 40.5%, and Alzheimer disease (AD) pathology in 19% of cases. Each variant was associated with 1 typical pathology; 24 of 29 (83%) svPPA showed FTLD-TDP type C, 22 of 25 (88%) nfvPPA showed FTLD-tau, and all 11 lvPPA had AD. Within FTLD-tau, 4R-tau pathology was commonly associated with nfvPPA, whereas Pick disease was observed in a minority of subjects across all variants except for lvPPA. Compared with pathologically typical cases, svPPA-tau showed significant extrapyramidal signs, greater executive impairment, and severe striatal and frontal GM and WM atrophy. nfvPPA-TDP patients lacked general motor symptoms or significant WM atrophy. Combining GM and WM volumes, SVM analysis showed 92.7% accuracy to distinguish FTLD-tau and FTLD-TDP pathologies across variants. Interpretation Each PPA clinical variant is associated with a typical and most frequent cognitive, neuroimaging, and neuropathological profile. Specific clinical and early anatomical features may suggest rare and atypical pathological diagnosis in vivo. Ann Neurol 2017;81:430–443

Pathological Tau Strains from Human Brains Recapitulate the Diversity of Tauopathies in Nontransgenic Mouse Brain.

Abstract: Pathological tau aggregates occur in Alzheimer's disease (AD) and other neurodegenerative tauopathies. It is not clearly understood why tauopathies vary greatly in the neuroanatomical and histopathological patterns of tau aggregation, which contribute to clinical heterogeneity in these disorders. Recent studies have shown that tau aggregates may form distinct structural conformations, known as tau strains. Here, we developed a novel model to test the hypothesis that cell-to-cell transmission of different tau strains occurs in nontransgenic (non-Tg) mice, and to investigate whether there are strain-specific differences in the pattern of tau transmission. By injecting pathological tau extracted from postmortem brains of AD (AD-tau), progressive supranuclear palsy (PSP-tau), and corticobasal degeneration (CBD-tau) patients into different brain regions of female non-Tg mice, we demonstrated the induction and propagation of endogenous mouse tau aggregates. Specifically, we identified differences in tau strain potency between AD-tau, CBD-tau, and PSP-tau in non-Tg mice. Moreover, differences in cell-type specificity of tau aggregate transmission were observed between tau strains such that only PSP-tau and CBD-tau strains induce astroglial and oligodendroglial tau inclusions, recapitulating the diversity of neuropathology in human tauopathies. Furthermore, we demonstrated that the neuronal connectome, but not the tau strain, determines which brain regions develop tau pathology. Finally, CBD-tau- and PSP-tau-injected mice showed spatiotemporal transmission of glial tau pathology, suggesting glial tau transmission contributes to the progression of tauopathies. Together, our data suggest that different tau strains determine seeding potency and cell-type specificity of tau aggregation that underlie the diversity of human tauopathies.SIGNIFICANCE STATEMENT Tauopathies show great clinical and neuropathological heterogeneity, despite the fact that tau aggregates in each disease. This heterogeneity could be due to tau aggregates forming distinct structural conformations, or strains. We now report the development of a sporadic tauopathy model to study human tau strains by intracerebrally injecting nontransgenic mice with pathological tau enriched from human tauopathy brains. We show human tau strains seed different types and cellular distributions of tau neuropathology in our model that recapitulate the heterogeneity seen in these human diseases.

The Alzheimer's Disease Neuroimaging Initiative 3: Continued innovation for clinical trial improvement

Abstract: Introduction The overall goal of the Alzheimer's Disease Neuroimaging Initiative (ADNI) is to validate biomarkers for Alzheimer's disease (AD) clinical trials. ADNI-3, which began on August 1, 2016, is a 5-year renewal of the current ADNI-2 study. Methods ADNI-3 will follow current and additional subjects with normal cognition, mild cognitive impairment, and AD using innovative technologies such as tau imaging, magnetic resonance imaging sequences for connectivity analyses, and a highly automated immunoassay platform and mass spectroscopy approach for cerebrospinal fluid biomarker analysis. A Systems Biology/pathway approach will be used to identify genetic factors for subject selection/enrichment. Amyloid positron emission tomography scanning will be standardized using the Centiloid method. The Brain Health Registry will help recruit subjects and monitor subject cognition. Results Multimodal analyses will provide insight into AD pathophysiology and disease progression. Discussion ADNI-3 will aim to inform AD treatment trials and facilitate development of AD disease-modifying treatments.

Poly(GP) proteins are a useful pharmacodynamic marker for C9ORF72-associated amyotrophic lateral sclerosis

Abstract: There is no effective treatment for amyotrophic lateral sclerosis (ALS), a devastating motor neuron disease. However, discovery of a G4C2 repeat expansion in the C9ORF72 gene as the most common genetic cause of ALS has opened up new avenues for therapeutic intervention for this form of ALS. G4C2 repeat expansion RNAs and proteins of repeating dipeptides synthesized from these transcripts are believed to play a key role in C9ORF72-associated ALS (c9ALS). Therapeutics that target G4C2 RNA, such as antisense oligonucleotides (ASOs) and small molecules, are thus being actively investigated. A limitation in moving such treatments from bench to bedside is a lack of pharmacodynamic markers for use in clinical trials. We explored whether poly(GP) proteins translated from G4C2 RNA could serve such a purpose. Poly(GP) proteins were detected in cerebrospinal fluid (CSF) and in peripheral blood mononuclear cells from c9ALS patients and, notably, from asymptomatic C9ORF72 mutation carriers. Moreover, CSF poly(GP) proteins remained relatively constant over time, boding well for their use in gauging biochemical responses to potential treatments. Treating c9ALS patient cells or a mouse model of c9ALS with ASOs that target G4C2 RNA resulted in decreased intracellular and extracellular poly(GP) proteins. This decrease paralleled reductions in G4C2 RNA and downstream G4C2 RNA-mediated events. These findings indicate that tracking poly(GP) proteins in CSF could provide a means to assess target engagement of G4C2 RNA-based therapies in symptomatic C9ORF72 repeat expansion carriers and presymptomatic individuals who are expected to benefit from early therapeutic intervention.

Recent publications from the Alzheimer's Disease Neuroimaging Initiative: Reviewing progress toward improved AD clinical trials

Abstract: Introduction The Alzheimer's Disease Neuroimaging Initiative (ADNI) has continued development and standardization of methodologies for biomarkers and has provided an increased depth and breadth of data available to qualified researchers. This review summarizes the over 400 publications using ADNI data during 2014 and 2015. Methods We used standard searches to find publications using ADNI data. Results (1) Structural and functional changes, including subtle changes to hippocampal shape and texture, atrophy in areas outside of hippocampus, and disruption to functional networks, are detectable in presymptomatic subjects before hippocampal atrophy; (2) In subjects with abnormal β-amyloid deposition (Aβ+), biomarkers become abnormal in the order predicted by the amyloid cascade hypothesis; (3) Cognitive decline is more closely linked to tau than Aβ deposition; (4) Cerebrovascular risk factors may interact with Aβ to increase white-matter (WM) abnormalities which may accelerate Alzheimer's disease (AD) progression in conjunction with tau abnormalities; (5) Different patterns of atrophy are associated with impairment of memory and executive function and may underlie psychiatric symptoms; (6) Structural, functional, and metabolic network connectivities are disrupted as AD progresses. Models of prion-like spreading of Aβ pathology along WM tracts predict known patterns of cortical Aβ deposition and declines in glucose metabolism; (7) New AD risk and protective gene loci have been identified using biologically informed approaches; (8) Cognitively normal and mild cognitive impairment (MCI) subjects are heterogeneous and include groups typified not only by "classic" AD pathology but also by normal biomarkers, accelerated decline, and suspected non-Alzheimer's pathology; (9) Selection of subjects at risk of imminent decline on the basis of one or more pathologies improves the power of clinical trials; (10) Sensitivity of cognitive outcome measures to early changes in cognition has been improved and surrogate outcome measures using longitudinal structural magnetic resonance imaging may further reduce clinical trial cost and duration; (11) Advances in machine learning techniques such as neural networks have improved diagnostic and prognostic accuracy especially in challenges involving MCI subjects; and (12) Network connectivity measures and genetic variants show promise in multimodal classification and some classifiers using single modalities are rivaling multimodal classifiers. Discussion Taken together, these studies fundamentally deepen our understanding of AD progression and its underlying genetic basis, which in turn informs and improves clinical trial design.

Clinicopathological correlations in behavioural variant frontotemporal dementia.

Abstract: Accurately predicting the underlying neuropathological diagnosis in patients with behavioural variant frontotemporal dementia (bvFTD) poses a daunting challenge for clinicians but will be critical for the success of disease-modifying therapies. We sought to improve pathological prediction by exploring clinicopathological correlations in a large bvFTD cohort. Among 438 patients in whom bvFTD was either the top or an alternative possible clinical diagnosis, 117 had available autopsy data, including 98 with a primary pathological diagnosis of frontotemporal lobar degeneration (FTLD), 15 with Alzheimer's disease, and four with amyotrophic lateral sclerosis who lacked neurodegenerative disease-related pathology outside of the motor system. Patients with FTLD were distributed between FTLD-tau (34 patients: 10 corticobasal degeneration, nine progressive supranuclear palsy, eight Pick's disease, three frontotemporal dementia with parkinsonism associated with chromosome 17, three unclassifiable tauopathy, and one argyrophilic grain disease); FTLD-TDP (55 patients: nine type A including one with motor neuron disease, 27 type B including 21 with motor neuron disease, eight type C with right temporal lobe presentations, and 11 unclassifiable including eight with motor neuron disease), FTLD-FUS (eight patients), and one patient with FTLD-ubiquitin proteasome system positive inclusions (FTLD-UPS) that stained negatively for tau, TDP-43, and FUS. Alzheimer's disease was uncommon (6%) among patients whose only top diagnosis during follow-up was bvFTD. Seventy-nine per cent of FTLD-tau, 86% of FTLD-TDP, and 88% of FTLD-FUS met at least 'possible' bvFTD diagnostic criteria at first presentation. The frequency of the six core bvFTD diagnostic features was similar in FTLD-tau and FTLD-TDP, suggesting that these features alone cannot be used to separate patients by major molecular class. Voxel-based morphometry revealed that nearly all pathological subgroups and even individual patients share atrophy in anterior cingulate, frontoinsula, striatum, and amygdala, indicating that degeneration of these regions is intimately linked to the behavioural syndrome produced by these diverse aetiologies. In addition to these unifying features, symptom profiles also differed among pathological subtypes, suggesting distinct anatomical vulnerabilities and informing a clinician's prediction of pathological diagnosis. Data-driven classification into one of the 10 most common pathological diagnoses was most accurate (up to 60.2%) when using a combination of known predictive factors (genetic mutations, motor features, or striking atrophy patterns) and the results of a discriminant function analysis that incorporated clinical, neuroimaging, and neuropsychological data.

Distinct binding of PET ligands PBB3 and AV-1451 to tau fibril strains in neurodegenerative tauopathies

Abstract: Diverse neurodegenerative disorders are characterized by deposition of tau fibrils composed of conformers (i.e. strains) unique to each illness. The development of tau imaging agents has enabled visualization of tau lesions in tauopathy patients, but the modes of their binding to different tau strains remain elusive. Here we compared binding of tau positron emission tomography ligands, PBB3 and AV-1451, by fluorescence, autoradiography and homogenate binding assays with homologous and heterologous blockades using tauopathy brain samples. Fluorescence microscopy demonstrated intense labelling of non-ghost and ghost tangles with PBB3 and AV-1451, while dystrophic neurites were more clearly detected by PBB3 in brains of Alzheimer's disease and diffuse neurofibrillary tangles with calcification, characterized by accumulation of all six tau isoforms. Correspondingly, partially distinct distributions of autoradiographic labelling of Alzheimer's disease slices with 11C-PBB3 and 18F-AV-1451 were noted. Neuronal and glial tau lesions comprised of 4-repeat isoforms in brains of progressive supranuclear palsy, corticobasal degeneration and familial tauopathy due to N279K tau mutation and 3-repeat isoforms in brains of Pick's disease and familial tauopathy due to G272V tau mutation were sensitively detected by PBB3 fluorescence in contrast to very weak AV-1451 signals. This was in line with moderate 11C-PBB3 versus faint 18F-AV-1451 autoradiographic labelling of these tissues. Radioligand binding to brain homogenates revealed multiple binding components with differential affinities for 11C-PBB3 and 18F-AV-1451, and higher availability of binding sites on progressive supranuclear palsy tau deposits for 11C-PBB3 than 18F-AV-1451. Our data indicate distinct selectivity of PBB3 compared to AV-1451 for diverse tau fibril strains. This highlights the more robust ability of PBB3 to capture wide-range tau pathologies.

Transethnic genome-wide scan identifies novel Alzheimer's disease loci

Abstract: Introduction Genetic loci for Alzheimer's disease (AD) have been identified in whites of European ancestry, but the genetic architecture of AD among other populations is less understood. Methods We conducted a transethnic genome-wide association study (GWAS) for late-onset AD in Stage 1 sample including whites of European Ancestry, African-Americans, Japanese, and Israeli-Arabs assembled by the Alzheimer's Disease Genetics Consortium. Suggestive results from Stage 1 from novel loci were followed up using summarized results in the International Genomics Alzheimer's Project GWAS dataset. Results Genome-wide significant (GWS) associations in single-nucleotide polymorphism (SNP)–based tests ( P −8 ) were identified for SNPs in PFDN1/HBEGF , USP6NL/ECHDC3 , and BZRAP1-AS1 and for the interaction of the (apolipoprotein E) APOE e4 allele with NFIC SNP. We also obtained GWS evidence ( P −6 ) for gene-based association in the total sample with a novel locus, TPBG ( P = 1.8 × 10 −6 ). Discussion Our findings highlight the value of transethnic studies for identifying novel AD susceptibility loci.

Expansion of the classification of FTLD-TDP: distinct pathology associated with rapidly progressive frontotemporal degeneration

Abstract: Frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP) can typically be categorized into one of four distinct histopathologic patterns of TDP-43 pathology, types A to D. The strength of this histopathologic classification lies in the association between FTLD-TDP subtypes and various clinical and genetic features of disease. Seven cases of FTLD-TDP were identified here which were difficult to classify based on existing pathologic criteria. Distinct features common to these cases included TDP-43 aggregates over a wide neuroanatomic distribution comprised of granulofilamentous neuronal inclusions, abundant grains, and oligodendroglial inclusions. TDP-43 aggregates were phosphorylated and associated with loss of normal nuclear TDP-43 protein (nuclear clearance) but were negative for ubiquitin. Biochemical analysis confirmed the presence of insoluble and phosphorylated TDP-43 and also revealed a distinct pattern of TDP-43 C-terminal fragments relative to other FTLD-TDP subtypes. Finally, these cases were uniformly associated with a very rapid clinical course culminating in death within ~3 years of disease onset. We suggest that these cases may represent a unique clinicopathologic subtype of FTLD-TDP which we provisionally call “type E.” The immature appearance of TDP-43 aggregates, widespread distribution, uniform biochemical profile and rapid clinical course highlights the clinical and pathologic variability within FTLD-TDP, and raises the possibility that type E neuropathology is the sequelae of a particularly virulent strain of TDP-43 proteinopathy.

Modeling Parkinson’s disease pathology by combination of fibril seeds and α-synuclein overexpression in the rat brain

Abstract: Although a causative role of α-synuclein (α-syn) is well established in Parkinson’s disease pathogenesis, available animal models of synucleinopathy do not replicate the full range of cellular and behavioral changes characteristic of the human disease. This study was designed to generate a more faithful model of Parkinson’s disease by injecting human α-syn fibril seeds into the rat substantia nigra (SN), in combination with adenoassociated virus (AAV)-mediated overexpression of human α-syn, at levels that, by themselves, are unable to induce acute dopamine (DA) neurodegeneration. We show that the ability of human α-syn fibrils to trigger Lewy-like α-synuclein pathology in the affected DA neurons is dramatically enhanced in the presence of elevated levels of human α-syn. This synucleinopathy was fully developed already 10 days after fibril injection, accompanied by progressive degeneration of dopaminergic neurons in SN, neuritic swelling, reduced striatal DA release, and impaired motor behavior. Moreover, a prominent inflammatory response involving both activation of resident microglia and infiltration of CD4+ and CD8+ T lymphocytes was observed. Hypertrophic microglia were found to enclose or engulf cells and processes containing Lewy-like α-syn aggregates. α-Syn aggregates were also observed inside these cells, suggesting transfer of phosphorylated α-syn from the affected nigral neurons. The nigral pathology triggered by fibrils in combination with AAV-mediated overexpression of α-syn reproduced many of the cardinal features of the human disease. The short time span and the distinct sequence of pathological and degenerative changes make this combined approach attractive as an experimental model for the assessment of neuroprotective and disease-modifying strategies.

Circulating brain-enriched microRNAs as novel biomarkers for detection and differentiation of neurodegenerative diseases

Abstract: Minimally invasive specific biomarkers of neurodegenerative diseases (NDs) would facilitate patient selection and disease progression monitoring. We describe the assessment of circulating brain-enriched microRNAs as potential biomarkers for Alzheimer’s disease (AD), frontotemporal dementia (FTD), Parkinson’s disease (PD), and amyotrophic lateral sclerosis (ALS). In this case-control study, the plasma samples were collected from 250 research participants with a clinical diagnosis of AD, FTD, PD, and ALS, as well as from age- and sex-matched control subjects (n = 50 for each group), recruited from 2003 to 2015 at the University of Pennsylvania Health System, including the Alzheimer’s Disease Center, the Parkinson’s Disease and Movement Disorders Center, the Frontotemporal Degeneration Center, and the Amyotrophic Lateral Sclerosis Clinic. Each group was randomly divided into training and confirmation sets of equal size. To evaluate the potential of circulating microRNAs enriched in specific brain regions affected by NDs and present in synapses as biomarkers of NDs, the levels of 37 brain-enriched and inflammation-associated microRNAs in the plasma of all participants were measured using individual qRT-PCR. A “microRNA pair” approach was used for data normalization. MicroRNA pairs and their combinations (classifiers) capable of differentiating NDs from control and from each other were defined using independently and jointly analyzed training and confirmation datasets. AD, PD, FTD, and ALS are differentiated from control with accuracy of 0.89, 0.90, 0.88, and 0.83 (AUCs, 0.96, 0.96, 0.94, and 0.93), respectively; NDs are differentiated from each other with accuracy ranging from 0.77 (AUC, 0.87) for AD vs. FTD to 0.93 (AUC, 0.98) for AD vs. ALS. The data further indicate sex dependence of some microRNA markers. The average increase in accuracy in distinguishing ND from control for all and male/female groups is 0.06; the largest increase is for ALS, from 0.83 for all participants to 0.92/0.98 for male/female participants. The work presented here suggests the possibility of developing microRNA-based diagnostics for detection and differentiation of NDs. Larger multicenter clinical studies are needed to further evaluate circulating brain-enriched microRNAs as biomarkers for NDs and to investigate their association with other ND biomarkers in clinical trial settings.

Genome-wide association study identifies four novel loci associated with Alzheimer's endophenotypes and disease modifiers

Abstract: More than 20 genetic loci have been associated with risk for Alzheimer’s disease (AD), but reported genome-wide significant loci do not account for all the estimated heritability and provide little information about underlying biological mechanisms. Genetic studies using intermediate quantitative traits such as biomarkers, or endophenotypes, benefit from increased statistical power to identify variants that may not pass the stringent multiple test correction in case–control studies. Endophenotypes also contain additional information helpful for identifying variants and genes associated with other aspects of disease, such as rate of progression or onset, and provide context to interpret the results from genome-wide association studies (GWAS). We conducted GWAS of amyloid beta (Aβ42), tau, and phosphorylated tau (ptau181) levels in cerebrospinal fluid (CSF) from 3146 participants across nine studies to identify novel variants associated with AD. Five genome-wide significant loci (two novel) were associated with ptau181, including loci that have also been associated with AD risk or brain-related phenotypes. Two novel loci associated with Aβ42 near GLIS1 on 1p32.3 (β = −0.059, P = 2.08 × 10−8) and within SERPINB1 on 6p25 (β = −0.025, P = 1.72 × 10−8) were also associated with AD risk (GLIS1: OR = 1.105, P = 3.43 × 10−2), disease progression (GLIS1: β = 0.277, P = 1.92 × 10−2), and age at onset (SERPINB1: β = 0.043, P = 4.62 × 10−3). Bioinformatics indicate that the intronic SERPINB1 variant (rs316341) affects expression of SERPINB1 in various tissues, including the hippocampus, suggesting that SERPINB1 influences AD through an Aβ-associated mechanism. Analyses of known AD risk loci suggest CLU and FERMT2 may influence CSF Aβ42 (P = 0.001 and P = 0.009, respectively) and the INPP5D locus may affect ptau181 levels (P = 0.009); larger studies are necessary to verify these results. Together the findings from this study can be used to inform future AD studies.

Multiple modality biomarker prediction of cognitive impairment in prospectively followed de novo Parkinson disease

Abstract: Objectives To assess the neurobiological substrate of initial cognitive decline in Parkinson’s disease (PD) to inform patient management, clinical trial design, and development of treatments Methods We longitudinally assessed, up to 3 years, 423 newly diagnosed patients with idiopathic PD, untreated at baseline, from 33 international movement disorder centers Study outcomes were four determinations of cognitive impairment or decline, and biomarker predictors were baseline dopamine transporter (DAT) single photon emission computed tomography (SPECT) scan, structural magnetic resonance imaging (MRI; volume and thickness), diffusion tensor imaging (mean diffusivity and fractional anisotropy), cerebrospinal fluid (CSF; amyloid beta [Aβ], tau and alpha synuclein), and 11 single nucleotide polymorphisms (SNPs) previously associated with PD cognition Additionally, longitudinal structural MRI and DAT scan data were included Univariate analyses were run initially, with false discovery rate = 02, to select biomarker variables for inclusion in multivariable longitudinal mixed-effect models Results By year 3, cognitive impairment was diagnosed in 15–38% participants depending on the criteria applied Biomarkers, some longitudinal, predicting cognitive impairment in multivariable models were: (1) dopamine deficiency (decreased caudate and putamen DAT availability); (2) diffuse, cortical decreased brain volume or thickness (frontal, temporal, parietal, and occipital lobe regions); (3) co-morbid Alzheimer’s disease Aβ amyloid pathology (lower CSF Aβ 1–42); and (4) genes (COMT val/val and BDNF val/val genotypes) Conclusions Cognitive impairment in PD increases in frequency 50–200% in the first several years of disease, and is independently predicted by biomarker changes related to nigrostriatal or cortical dopaminergic deficits, global atrophy due to possible widespread effects of neurodegenerative disease, co-morbid Alzheimer’s disease plaque pathology, and genetic factors

Genetic correlation between amyotrophic lateral sclerosis and schizophrenia

Abstract: We have previously shown higher-than-expected rates of schizophrenia in relatives of patients with amyotrophic lateral sclerosis (ALS), suggesting an aetiological relationship between the diseases. Here, we investigate the genetic relationship between ALS and schizophrenia using genome-wide association study data from over 100,000 unique individuals. Using linkage disequilibrium score regression, we estimate the genetic correlation between ALS and schizophrenia to be 14.3% (7.05-21.6; P=1 × 10-4) with schizophrenia polygenic risk scores explaining up to 0.12% of the variance in ALS (P=8.4 × 10-7). A modest increase in comorbidity of ALS and schizophrenia is expected given these findings (odds ratio 1.08-1.26) but this would require very large studies to observe epidemiologically. We identify five potential novel ALS-associated loci using conditional false discovery rate analysis. It is likely that shared neurobiological mechanisms between these two disorders will engender novel hypotheses in future preclinical and clinical studies.

Clinical marker for Alzheimer disease pathology in logopenic primary progressive aphasia

Abstract: Objective: To determine whether logopenic features of phonologic loop dysfunction reflect Alzheimer disease (AD) neuropathology in primary progressive aphasia (PPA). Methods: We performed a retrospective case-control study of 34 patients with PPA with available autopsy tissue. We compared baseline and longitudinal clinical features in patients with primary AD neuropathology to those with primary non-AD pathologies. We analyzed regional neuroanatomic disease burden in pathology-defined groups using postmortem neuropathologic data. Results: A total of 19/34 patients had primary AD pathology and 15/34 had non-AD pathology (13 frontotemporal lobar degeneration, 2 Lewy body disease). A total of 16/19 (84%) patients with AD had a logopenic spectrum phenotype; 5 met published criteria for the logopenic variant (lvPPA), 8 had additional grammatical or semantic deficits (lvPPA+), and 3 had relatively preserved sentence repetition (lvPPA−). Sentence repetition was impaired in 68% of patients with PPA with AD pathology; forward digit span (DF) was impaired in 90%, substantially higher than in non-AD PPA (33%, p p p ≤ 0.03). Conclusions: Phonologic loop dysfunction is a central feature of AD-associated PPA and specifically correlates with temporoparietal neurodegeneration. Quantitative measures of phonologic loop function, combined with modified clinical lvPPA criteria, may help discriminate AD-associated PPA.

Longitudinal CSF biomarkers in patients with early Parkinson disease and healthy controls

Abstract: Objective: To analyze longitudinal levels of CSF biomarkers in drug-naive patients with Parkinson disease (PD) and healthy controls (HC), examine the extent to which these biomarker changes relate to clinical measures of PD, and identify what may influence them. Methods: CSF α-synuclein (α-syn), total and phosphorylated tau (t- and p-tau), and β-amyloid 1–42 (Aβ42) were measured at baseline and 6 and 12 months in 173 patients with PD and 112 matched HC in the international multicenter Parkinson9s Progression Marker Initiative. Baseline clinical and demographic variables, PD medications, neuroimaging, and genetic variables were evaluated as potential predictors of CSF biomarker changes. Results: CSF biomarkers were stable over 6 and 12 months, and there was a small but significant increase in CSF Aβ42 in both patients with patients with PD and HC from baseline to 12 months. The t-tau remained stable. The p-tau increased marginally more in patients with PD than in HC. α-syn remained relatively stable in patients with PD and HC. Ratios of p-tau/t-tau increased, while t-tau/Aβ42 decreased over 12 months in patients with PD. CSF biomarker changes did not correlate with changes in Movement Disorder Society–sponsored revision of the Unified Parkinson’s Disease Rating Scale motor scores or dopamine imaging. CSF α-syn levels at 12 months were lower in patients with PD treated with dopamine replacement therapy, especially dopamine agonists. Conclusions: These core CSF biomarkers remained stable over 6 and 12 months in patients with early PD and HC. PD medication use may influence CSF α-syn. Novel biomarkers are needed to better profile progressive neurodegeneration in PD.

Evaluating the Patterns of Aging-Related Tau Astrogliopathy Unravels Novel Insights Into Brain Aging and Neurodegenerative Diseases.

Abstract: The term "aging-related tau astrogliopathy" (ARTAG) describes pathological accumulation of abnormally phosphorylated tau protein in astrocytes. We evaluated the correlates of ARTAG types (i.e., subpial, subependymal, white and gray matter, and perivascular) in different neuroanatomical regions. Clinical, neuropathological, and genetic (eg, APOE e4 allele, MAPT H1/H2 haplotype) data from 628 postmortem brains from subjects were investigated; most of the patients had been longitudinally followed at the University of Pennsylvania. We found that (i) the amygdala is a hotspot for all ARTAG types; (ii) age at death, male sex, and presence of primary frontotemporal lobar degeneration (FTLD) tauopathy are significantly associated with ARTAG; (iii) age at death, greater degree of brain atrophy, ventricular enlargement, and Alzheimer disease (AD)-related variables are associated with subpial, white matter, and perivascular ARTAG types; (iv) AD-related variables are associated particularly with lobar white matter ARTAG; and (v) gray matter ARTAG in primary FTLD-tauopathies appears in areas without neuronal tau pathology. We provide a reference map of ARTAG types and propose at least 5 constellations of ARTAG. Furthermore, we propose a conceptual link between primary FTLD-tauopathy and ARTAG-related astrocytic tau pathologies. Our observations serve as a basis for etiological stratification and definition of progression patterns of ARTAG.

Phosphorylated neurofilament heavy chain: A biomarker of survival for C9ORF72-associated amyotrophic lateral sclerosis

Abstract: As potential treatments for C9ORF72-associated amyotrophic lateral sclerosis (c9ALS) approach clinical trials, the identification of prognostic biomarkers for c9ALS becomes a priority. We show that levels of phosphorylated neurofilament heavy chain (pNFH) in cerebrospinal fluid (CSF) predict disease status and survival in c9ALS patients, and are largely stable over time. Moreover, c9ALS patients exhibit higher pNFH levels, more rapid disease progression, and shorter survival after disease onset than ALS patients without C9ORF72 expansions. These data support the use of CSF pNFH as a prognostic biomarker for clinical trials, which will increase the likelihood of successfully developing a treatment for c9ALS. Ann Neurol 2017;82:139-146.

Clinicopathological correlations in behavioural variant frontotemporal dementia

Abstract: Accurately predicting the underlying neuropathological diagnosis in patients with behavioural variant frontotemporal dementia (bvFTD) poses a daunting challenge for clinicians but will be critical for the success of disease-modifying therapies. We sought to improve pathological prediction by exploring clinicopathological correlations in a large bvFTD cohort. Among 438 patients in whom bvFTD was either the top or an alternative possible clinical diagnosis, 117 had available autopsy data, including 98 with a primary pathological diagnosis of frontotemporal lobar degeneration (FTLD), 15 with Alzheimer's disease, and four with amyotrophic lateral sclerosis who lacked neurodegenerative disease-related pathology outside of the motor system. Patients with FTLD were distributed between FTLD-tau (34 patients: 10 corticobasal degeneration, nine progressive supranuclear palsy, eight Pick's disease, three frontotemporal dementia with parkinsonism associated with chromosome 17, three unclassifiable tauopathy, and one argyrophilic grain disease); FTLD-TDP (55 patients: nine type A including one with motor neuron disease, 27 type B including 21 with motor neuron disease, eight type C with right temporal lobe presentations, and 11 unclassifiable including eight with motor neuron disease), FTLD-FUS (eight patients), and one patient with FTLD-ubiquitin proteasome system positive inclusions (FTLD-UPS) that stained negatively for tau, TDP-43, and FUS. Alzheimer's disease was uncommon (6%) among patients whose only top diagnosis during follow-up was bvFTD. Seventy-nine per cent of FTLD-tau, 86% of FTLD-TDP, and 88% of FTLD-FUS met at least 'possible' bvFTD diagnostic criteria at first presentation. The frequency of the six core bvFTD diagnostic features was similar in FTLD-tau and FTLD-TDP, suggesting that these features alone cannot be used to separate patients by major molecular class. Voxel-based morphometry revealed that nearly all pathological subgroups and even individual patients share atrophy in anterior cingulate, frontoinsula, striatum, and amygdala, indicating that degeneration of these regions is intimately linked to the behavioural syndrome produced by these diverse aetiologies. In addition to these unifying features, symptom profiles also differed among pathological subtypes, suggesting distinct anatomical vulnerabilities and informing a clinician's prediction of pathological diagnosis. Data-driven classification into one of the 10 most common pathological diagnoses was most accurate (up to 60.2%) when using a combination of known predictive factors (genetic mutations, motor features, or striking atrophy patterns) and the results of a discriminant function analysis that incorporated clinical, neuroimaging, and neuropsychological data.

Protein astrogliopathies in human neurodegenerative diseases and aging

Abstract: Neurodegenerative diseases are characterized by progressive dysfunction and loss of neurons associated with depositions of pathologically altered proteins showing hierarchical involvement of brain regions. The role of astrocytes in the pathogenesis of neurodegenerative diseases is explored as contributors to neuronal degeneration or neuroprotection pathways, and also as potential mediators of the transcellular spreading of disease-associated proteins. Protein astrogliopathy (PAG), including deposition of amyloid-β, prion protein, tau, α-synuclein, and very rarely transactive response DNA-binding protein 43 (TDP-43) is not unprecedented or unusual in neurodegenerative diseases. Morphological characterization of PAG is considered, however, only for the neuropathological diagnosis and classification of tauopathies. Astrocytic tau pathology is seen in primary frontotemporal lobar degeneration (FTLD) associated with tau pathologies (FTLD-Tau), and also in the form of aging-related tau astrogliopathy (ARTAG). Importantly, ARTAG shares common features with primary FTLD-Tau as well as with the astroglial tau pathologies that are thought to be hallmarks of a brain injury-related tauopathy known as chronic traumatic encephalopathy (CTE). Supported by experimental observations, the morphological variability of PAG might reflect distinct pathogenic involvement of different astrocytic populations. PAG might indicate astrocytic contribution to spreading or clearance of disease-associated proteins, however, this might lead to astrocytic dysfunction and eventually contribute to the degeneration of neurons. Here, we review recent advances in understanding ARTAG and other related forms of PAG.

Genome-wide, high-content siRNA screening identifies the Alzheimer’s genetic risk factor FERMT2 as a major modulator of APP metabolism

Abstract: Genome-wide association studies (GWASs) have identified 19 susceptibility loci for Alzheimer’s disease (AD). However, understanding how these genes are involved in the pathophysiology of AD is one of the main challenges of the “post-GWAS” era. At least 123 genes are located within the 19 susceptibility loci; hence, a conventional approach (studying the genes one by one) would not be time- and cost-effective. We therefore developed a genome-wide, high-content siRNA screening approach and used it to assess the functional impact of gene under-expression on APP metabolism. We found that 832 genes modulated APP metabolism. Eight of these genes were located within AD susceptibility loci. Only FERMT2 (a β3-integrin co-activator) was also significantly associated with a variation in cerebrospinal fluid Aβ peptide levels in 2886 AD cases. Lastly, we showed that the under-expression of FERMT2 increases Aβ peptide production by raising levels of mature APP at the cell surface and facilitating its recycling. Taken as a whole, our data suggest that FERMT2 modulates the AD risk by regulating APP metabolism and Aβ peptide production.