Qualification of the analytical and clinical performance of CSF biomarker analyses in ADNI.


:The close correlation between abnormally low pre-mortem cerebrospinal fluid (CSF) concentrations of amyloid-β1-42 (Aβ(1-42)) and plaque burden measured by amyloid imaging as well as between pathologically increased levels of CSF tau and the extent of neurodegeneration measured by MRI has led to growing interest in using these biomarkers to predict the presence of AD plaque and tangle pathology. A challenge for the widespread use of these CSF biomarkers is the high variability in the assays used to measure these analytes which has been ascribed to multiple pre-analytical and analytical test performance factors. To address this challenge, we conducted a seven-center inter-laboratory standardization study for CSF total tau (t-tau), phospho-tau (p-tau(181)) and Aβ(1-42) as part of the Alzheimer's Disease Neuroimaging Initiative (ADNI). Aliquots prepared from five CSF pools assembled from multiple elderly controls (n = 3) and AD patients (n = 2) were the primary test samples analyzed in each of three analytical runs by the participating laboratories using a common batch of research use only immunoassay reagents (INNO-BIA AlzBio3, xMAP technology, from Innogenetics) on the Luminex analytical platform. To account for the combined effects on overall precision of CSF samples (fixed effect), different laboratories and analytical runs (random effects), these data were analyzed by mixed-effects modeling with the following results: within center %CV 95% CI values (mean) of 4.0-6.0% (5.3%) for CSF Aβ(1-42); 6.4-6.8% (6.7%) for t-tau and 5.5-18.0% (10.8%) for p-tau(181) and inter-center %CV 95% CI range of 15.9-19.8% (17.9%) for Aβ(1-42), 9.6-15.2% (13.1%) for t-tau and 11.3-18.2% (14.6%) for p-tau(181). Long-term experience by the ADNI biomarker core laboratory replicated this degree of within-center precision. Diagnostic threshold CSF concentrations for Aβ(1-42) and for the ratio t-tau/Aβ(1-42) were determined in an ADNI independent, autopsy-confirmed AD cohort from whom ante-mortem CSF was obtained, and a clinically defined group of cognitively normal controls (NCs) provides statistically significant separation of those who progressed from MCI to AD in the ADNI study. These data suggest that interrogation of ante-mortem CSF in cognitively impaired individuals to determine levels of t-tau, p-tau(181) and Aβ(1-42), together with MRI and amyloid imaging biomarkers, could replace autopsy confirmation of AD plaque and tangle pathology as the "gold standard" for the diagnosis of definite AD in the near future.


Acta Neuropathol


Acta neuropathologica


Shaw LM,Vanderstichele H,Knapik-Czajka M,Figurski M,Coart E,Blennow K,Soares H,Simon AJ,Lewczuk P,Dean RA,Siemers E,Potter W,Lee VM,Trojanowski JQ,Alzheimer's Disease Neuroimaging Initiative.




Has Abstract


2011-05-01 00:00:00












  • Argyrophilic plaque-like deposits in children.

    abstract::We recently examined the brain from an 8-month-old infant with Down's syndrome and found argyrophilic plaque-like deposits throughout the neocortex and cerebellum. To ascertain the specificity of this observation, we examined 27 additional brains from the pediatric autopsy service, including 1 from another patient wit...

    journal_title:Acta neuropathologica

    pub_type: 杂志文章


    authors: Crain BJ,McPhatter L,Croom DW 2nd,Hulette CM

    更新日期:1995-01-01 00:00:00

  • Progressive accumulation of ubiquitin and disappearance of alpha-synuclein epitope in multiple system atrophy-associated glial cytoplasmic inclusions: triple fluorescence study combined with Gallyas-Braak method.

    abstract::Alpha-synuclein (alphaS) and ubiquitin (Ub) are shared constituents of glial cytoplasmic inclusions (GCIs) and Lewy bodies (LBs), both composed of fibrillary structures. Staining profiles of GCIs were investigated with triple immunofluorescence involving immunostaining for alphaS and Ub, both amplified with catalyzed ...

    journal_title:Acta neuropathologica

    pub_type: 杂志文章


    authors: Sakamoto M,Uchihara T,Nakamura A,Mizutani T,Mizusawa H

    更新日期:2005-10-01 00:00:00

  • Protracted form of Canavan's disease: case history and protein kinase activity of membrane fractions.

    abstract::Clinical and morphological findings in an 8-year-old Jewish girl with spongy leukodystrophy are presented. Ultrastructural changes indicated that this may be a form of Canavan's disease with some atypical features. Biochemical measurements indicated that synaptosomal membranes prepared from the striatum but not from t...

    journal_title:Acta neuropathologica

    pub_type: 杂志文章


    authors: Boehme DH,Marks N

    更新日期:1981-01-01 00:00:00

  • Clofibrate-induced myopathy in the rat.

    abstract::Rats were given daily injections of 0.2 or 0.5 g/kg chlorophenoxyisobutyrate (clofibrate) for 9 to 46 days. Lower leg muscles were studied with light and electron microscopy. Daily treatment with 0.5 g/kg of the drug for 26--46 days caused myopathic changes. ...

    journal_title:Acta neuropathologica

    pub_type: 杂志文章


    authors: Teräväinen H,Larsen A,Hillbom M

    更新日期:1977-08-16 00:00:00

  • Response of the axon and barrier endothelium to experimental allergic neuritis induced by autoreactive T cell lines.

    abstract::Experimental allergic neuritis was induced in Lewis rats by inoculation with autoreactive T cell lines sensitized to residue 57-81 of P2 myelin protein. Control rats received cells derived from immunization to complete Freund's adjuvant alone. Endoneurial fluid pressure (EFP) was measured in both sciatic nerves at 0, ...

    journal_title:Acta neuropathologica

    pub_type: 杂志文章


    authors: Powell HC,Myers RR,Mizisin AP,Olee T,Brostoff SW

    更新日期:1991-01-01 00:00:00

  • Fine structural changes in the mutant hamster with hind leg paralysis.

    abstract::Various parts of the central and peripheral nervous system of the mutant hamster with hind leg paralysis were studied in the electron microscope. A number of alterations involving the myelin sheath, the axon and certain neuronal perikarya were observed. Anterior horn cells were apparently well preserved. This conditio...

    journal_title:Acta neuropathologica

    pub_type: 杂志文章


    authors: Hirano A

    更新日期:1977-08-31 00:00:00

  • Alterations of mGluR5 and its endogenous regulators Norbin, Tamalin and Preso1 in schizophrenia: towards a model of mGluR5 dysregulation.

    abstract::Knockout of genes encoding metabotropic glutamate receptor 5 (mGluR5) or its endogenous regulators, such as Norbin, induce a schizophrenia-like phenotype in rodents, suggesting dysregulation of mGluR5 in schizophrenia. Human genetic and pharmacological animal studies support this hypothesis, but no studies have explor...

    journal_title:Acta neuropathologica

    pub_type: 杂志文章


    authors: Matosin N,Fernandez-Enright F,Fung SJ,Lum JS,Engel M,Andrews JL,Huang XF,Weickert CS,Newell KA

    更新日期:2015-07-01 00:00:00

  • Expression of the cytokine leukemia inhibitory factor and pro-apoptotic insulin-like growth factor binding protein-3 in Alzheimer's disease.

    abstract::Amyloid-beta (Abeta) deposition in cerebral blood vessel walls is one of the key features of Alzheimer's disease (AD). Abeta(1-40) carrying the "Dutch" mutation (DAbeta(1-40)) induces rapid degeneration of cultured human brain pericytes (HBP). To study the mechanisms of this Abeta-induced toxicity, a comparative cDNA ...

    journal_title:Acta neuropathologica

    pub_type: 杂志文章


    authors: Rensink AA,Gellekink H,Otte-Höller I,ten Donkelaar HJ,de Waal RM,Verbeek MM,Kremer B

    更新日期:2002-11-01 00:00:00

  • Congenital lead encephalopathy in monkeys.

    abstract::Thirty-one squirrel monkey fetuses were exposed to lead acetate given to the mothers perorally during the last three-fourths or two-thirds of pregnancy. The mean maternal blood lead concentration of the group was 37 micrograms/100 ml and the individual means ranged from 22-82 micrograms/100 ml. Examination of the cent...

    journal_title:Acta neuropathologica

    pub_type: 杂志文章


    authors: Lögdberg B,Brun A,Berlin M,Schütz A

    更新日期:1988-01-01 00:00:00

  • MELAS: clinical phenotype and morphological brain abnormalities.

    abstract::We describe the clinical and neuropathological findings of three unrelated autopsy cases of MELAS harboring the A3243G transition in the mitochondrial DNA (mtDNA). Using immunohistochemical techniques, we studied the expression of several subunits of the respiratory chain in various brain regions from the same cases. ...

    journal_title:Acta neuropathologica

    pub_type: 杂志文章


    authors: Sparaco M,Simonati A,Cavallaro T,Bartolomei L,Grauso M,Piscioli F,Morelli L,Rizzuto N

    更新日期:2003-09-01 00:00:00

  • Localization of fused in sarcoma (FUS) protein to the post-synaptic density in the brain.

    abstract::Mutations in the fused in sarcoma (FUS) gene are linked to a form of familial amyotrophic lateral sclerosis (ALS), ALS6. The FUS protein is a major component of the ubiquitin-positive neuronal cytoplasmic inclusions in both ALS6 and some rare forms of frontotemporal lobar degeneration (FTLD). The latter are now collec...

    journal_title:Acta neuropathologica

    pub_type: 杂志文章


    authors: Aoki N,Higashi S,Kawakami I,Kobayashi Z,Hosokawa M,Katsuse O,Togo T,Hirayasu Y,Akiyama H

    更新日期:2012-09-01 00:00:00

  • Prion propagation estimated from brain diffusion MRI is subtype dependent in sporadic Creutzfeldt-Jakob disease.

    abstract::Sporadic Creutzfeldt-Jakob disease (sCJD) is a transmissible brain proteinopathy. Five main clinicopathological subtypes (sCJD-MM(V)1, -MM(V)2C, -MV2K, -VV1, and -VV2) are currently distinguished. Histopathological evidence suggests that the localisation of prion aggregates and spongiform lesions varies among subtypes...

    journal_title:Acta neuropathologica

    pub_type: 杂志文章


    authors: Pascuzzo R,Oxtoby NP,Young AL,Blevins J,Castelli G,Garbarino S,Cohen ML,Schonberger LB,Gambetti P,Appleby BS,Alexander DC,Bizzi A

    更新日期:2020-08-01 00:00:00

  • N-Hexane- and methylethylketone-induced polyneuropathy. Abnormal accumulation of glycogen in unmyelinated axons. Report of a case.

    abstract::This report presents the ultrastructural nerve study of a patient with sensorimotor neuropathy by a shoe glue containing an association of n-hexane and methylethylketone. Giant axons, distended by microfilamentous proliferation typical of such cases of neuropathy, were found in significant amounts. An unusual histolog...

    journal_title:Acta neuropathologica

    pub_type: 杂志文章


    authors: Vallat JM,Leboutet MJ,Loubet A,Piva C,Dumas M

    更新日期:1981-01-01 00:00:00

  • A simple method of rapid freezing adequately preserves brain tissue for immunocytochemistry, light and electron microscopic examination.

    abstract::A simple and reproducible method for cryopreservation of brain tissue from patients with Alzheimer's disease is described. Fresh brain slices (1 cm thick) obtained less than 6 h postmortem are placed in sealed plastic bags, sandwiched between 0.3-cm-thick aluminium sheets, and frozen by placing the entire "sandwich" b...

    journal_title:Acta neuropathologica

    pub_type: 杂志文章


    authors: Nochlin D,Mackenzie AP,Bryant EM,Norwood TH,Sumi SM

    更新日期:1993-01-01 00:00:00

  • Preponderance of sonic hedgehog pathway activation characterizes adult medulloblastoma.

    abstract::Medulloblastoma (MB) represents approximately 4% of adult brain tumours, and as such is a poorly studied disease. Although many adult MB are treated using paediatric MB protocols, the reported outcomes are inferior to those observed in children. It remains unclear whether biologic differences underlie these clinical o...

    journal_title:Acta neuropathologica

    pub_type: 杂志文章


    authors: Al-Halabi H,Nantel A,Klekner A,Guiot MC,Albrecht S,Hauser P,Garami M,Bognar L,Kavan P,Gerges N,Shirinian M,Roberge D,Muanza T,Jabado N

    更新日期:2011-02-01 00:00:00

  • Overexpression of human wild-type FUS causes progressive motor neuron degeneration in an age- and dose-dependent fashion.

    abstract::Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) are relentlessly progressive neurodegenerative disorders with overlapping clinical, genetic and pathological features. Cytoplasmic inclusions of fused in sarcoma (FUS) are the hallmark of several forms of FTLD and ALS patients with mutati...

    journal_title:Acta neuropathologica

    pub_type: 杂志文章


    authors: Mitchell JC,McGoldrick P,Vance C,Hortobagyi T,Sreedharan J,Rogelj B,Tudor EL,Smith BN,Klasen C,Miller CC,Cooper JD,Greensmith L,Shaw CE

    更新日期:2013-02-01 00:00:00

  • Selective localization of gelatinase A, an enzyme degrading beta-amyloid protein, in white matter microglia and in Schwann cells.

    abstract::Gelatinase A is an enzyme capable of cleaving soluble beta-amyloid protein (beta AP), and may function as an alpha-secretase to produce secretory forms of amyloid precursor protein. We examined gelatinase A immunoreactivity in the brains and posterior roots of neurologically normal, lacunar stroke, Alzheimer disease (...

    journal_title:Acta neuropathologica

    pub_type: 杂志文章


    authors: Yamada T,Miyazaki K,Koshikawa N,Takahashi M,Akatsu H,Yamamoto T

    更新日期:1995-01-01 00:00:00

  • Extracellular edema and glial response to it in the cerebellum of suckling rats with low-dose lead encephalopathy. An electron microscopic and immunohistochemical study.

    abstract::Newborn rats were exposed to daily intraperitoneal injections of 10 mg lead nitrate per kg body weight for the first 15 postnatal days. The growth and mortality of the lead-exposed animals did not differ from their control litter-mates, injected with vehicle only. In our previous studies, focal hemorrhages and spongy ...

    journal_title:Acta neuropathologica

    pub_type: 杂志文章


    authors: Sundström R,Kalimo H

    更新日期:1987-01-01 00:00:00

  • Niemann-Pick disease (Crocker's type C): A histological study of the distribution and qualitative differences fo the storage process.

    abstract::A histochemical study is reported of regional differences of the lipid storage in a case of Niemann-Pick disease (NPD) type C. Besides tissues known to be affected (reticulo-endothelium, hepatocytes, nervous system), storage was demonstrated in adrenal cortical spongiocytes, sweat glands, renal glomerular and tubular ...

    journal_title:Acta neuropathologica

    pub_type: 杂志文章


    authors: Elleder M,Jirásek A,Smíd F

    更新日期:1975-12-19 00:00:00

  • Splanchnic preganglionic neurons in man. I. Morphometry of preganglionic cytons.

    abstract::The thoracic sympathetic preganglionic outflow is important in the maintenance of postural normotension in man. Normative data on the intermediolateral column (ILC) neuron cell bodies is lacking. Counts and measurements on the right ILC cytons have been performed on the T6, T7 and T8 segments of 12 spinal cords of man...

    journal_title:Acta neuropathologica

    pub_type: 杂志文章


    authors: Low PA,Okazaki H,Dyck PJ

    更新日期:1977-09-26 00:00:00

  • In situ hybridization of myoglobin mRNA: results on the skeletal muscles of normal subjects and patients with neuromuscular diseases.

    abstract::The intracellular localization of myoglobin(Mb) mRNA in the skeletal muscles of normal subjects and patients with Duchenne muscular dystrophy(DMD) or amyotrophic lateral sclerosis(ALS) was examined by in situ hybridization using a biotin-labeled cDNA probe. In cross sections of normal muscles, Mb mRNA signals were dem...

    journal_title:Acta neuropathologica

    pub_type: 杂志文章


    authors: Mitsui T,Kawai H,Naruo T,Nishino H,Saito S

    更新日期:1993-01-01 00:00:00

  • Selective formation of certain advanced glycation end products in spinal cord astrocytes of humans and mice with superoxide dismutase-1 mutation.

    abstract::Recent studies have documented carbonyl stress involvement in the pathogenesis of sporadic amyotrophic lateral sclerosis (ALS). The aim of the present study was to assess a role for carbonyl stress in motor neuron degeneration associated with superoxide dismutase-1 (SOD1) mutant familial ALS and its transgenic mouse m...

    journal_title:Acta neuropathologica

    pub_type: 杂志文章


    authors: Shibata N,Hirano A,Hedley-Whyte ET,Dal Canto MC,Nagai R,Uchida K,Horiuchi S,Kawaguchi M,Yamamoto T,Kobayashi M

    更新日期:2002-08-01 00:00:00

  • Subclinical entrapment neuropathy of the equine suprascapular nerve.

    abstract::The suprascapular nerve from 14 horses, which had no clinical evidence of spinatus muscle atrophy, were obtained to determine whether the nerve was sub-clinically compressed at the scapular edge. The nerves were divided into three portions, proximal and distal to the scapular edge and as it reflected around it. In nin...

    journal_title:Acta neuropathologica

    pub_type: 杂志文章


    authors: Duncan ID,Schneider RK,Hammang JP

    更新日期:1987-01-01 00:00:00

  • Characterization of antibodies that selectively detect alpha-synuclein in pathological inclusions.

    abstract::Sensitive detection of alpha-synuclein (alpha-syn) pathology is important in the diagnosis of disorders like Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy and in providing better insights into the etiology of these diseases. Several monoclonal antibodies that selectively react with aggreg...

    journal_title:Acta neuropathologica

    pub_type: 杂志文章


    authors: Waxman EA,Duda JE,Giasson BI

    更新日期:2008-07-01 00:00:00

  • Type C retroviral expression in spontaneous feline olfactory neuroblastomas.

    abstract::Three cases of spontaneous olfactory neuroblastoma (ONB) in domestic cats were morphologically and immunocytochemically characterized. Diagnostic light microscopic features included Flexner and Homer-Wright rosettes, while ultrastructurally the cells had neuritic processes, intracellular intermediate filaments, and in...

    journal_title:Acta neuropathologica

    pub_type: 杂志文章


    authors: Schrenzel MD,Higgins RJ,Hinrichs SH,Smith MO,Torten M

    更新日期:1990-01-01 00:00:00

  • Excitatory amino acid transporter 1 and 2 immunoreactivity in the spinal cord in amyotrophic lateral sclerosis.

    abstract::The spinal cord of 20 patients with amyotrophic lateral sclerosis (ALS) and 5 patients with lower motor neuron disease (LMND) were investigated immunohistochemically using anti-human excitatory amino acid transporter 1 (EAAT1) and EAAT2 antibodies which are the astrocytic transporters. The purpose of the study was to ...

    journal_title:Acta neuropathologica

    pub_type: 杂志文章


    authors: Sasaki S,Komori T,Iwata M

    更新日期:2000-08-01 00:00:00

  • Ultrastructural aspects of muscle and nerve in Werdnig-Hoffmann disease.

    abstract::The authors describe in biopsies from 6 cases of Werdnig-Hoffmann disease, including 2 of the more benign type, the ultrastructural typical aspects of denervation. They compare their findings with those of other workers. The striking points are the great variation in the diameter of the muscle fibres and the myofibril...

    journal_title:Acta neuropathologica

    pub_type: 杂志文章


    authors: Szliwowski HB,Drochmans P

    更新日期:1975-01-01 00:00:00

  • Up-regulation of cyclooxygenase-2 in inflammatory demyelinating neuropathy.

    abstract::To clarify the role of prostaglandins in peripheral nerve demyelination, we examined the expression of cyclooxygenase-2 (COX-2) using selected nerve specimens from patients with chronic inflammatory demyelinating polyneuropathy. COX-2 protein was up-regulated in macrophages causing active demyelination. In situ hybrid...

    journal_title:Acta neuropathologica

    pub_type: 杂志文章


    authors: Kawasaki T,Oka N,Akiguchi I,Miyamoto K,Kaji R,Shibasaki H

    更新日期:2001-02-01 00:00:00

  • Thrombosis of a saccular microaneurysm causing cerebral (pontine) lacunae.

    abstract::The authors present the case of a hypertensive patient with a thrombosis of a saccular microaneurysm (SMA) and underlying cerebral (pontine) lacunae. This SMA lay at the junction between the main vessel and two small feeding arteries penetrating into the necrotic territory. Microhemorrhages were observed in and outsid...

    journal_title:Acta neuropathologica

    pub_type: 杂志文章


    authors: Benhaiem-Sigaux N,Gherardi R,Salama J,Gray F,Amouroux J,Poirier J

    更新日期:1986-01-01 00:00:00

  • "Reducing body"-like inclusions in skeletal muscle in childhood-onset acid maltase deficiency.

    abstract::Unusual inclusions with some of the features of "reducing bodies" were encountered in the skeletal muscle biopsy of a 2.5-year-old boy with childhood-onset acid maltase deficiency. The biopsy revealed a vacuolar myopathy with lysosomal storage of glycogen and eosinophilic refractile inclusions in myofibers, which appe...

    journal_title:Acta neuropathologica

    pub_type: 杂志文章


    authors: Jay V,Christodoulou J,Mercer-Connolly A,McInnes RR

    更新日期:1992-01-01 00:00:00