To facilitate meta-analysis, AlzBiomarker uses standardized terms to refer to biomarkers, disease conditions, and assay methods. For example, within the database, the biomarker term "Aβ42" may refer to data originally reported as Aβ_1-42 or Aβ42_x-42, depending on the epitopes of the antibodies used. See below for brief descriptions of the terms used in the database.

Biomarkers

Aβ38: Amyloid-beta38 is a peptide product of Amyloid Precursor Protein (APP) processing.

Aβ40 Amyloid-beta40 is a peptide product of APP. Within the database, Aβ40 refers to all forms of the peptide (e.g., Aβ40_1-40 and Aβ40_x-40) irrespective of the specific epitopes used for detection.

Aβ42: Amyloid-beta42 is a peptide product of APP. Within the database, Aβ42 refers to all forms of the peptide (e.g., Aβ42_1-42 and Aβ42_x-42) irrespective of the specific epitopes used for detection.

albumin ratio: a ratio of albumin in cerebrospinal fluid compared to levels in a blood fraction (either serum or plasma). Thought to reflect the functioning of the blood brain barrier.

GFAP: Glial fibrillary acidic protein is a intermediate filament protein enriched in reactive astrocytes.

hFABP: Fatty acid-binding protein, heart is a lipid-binding protein expressed in the brain. Synonyms: Fatty acid-binding protein 3, FABP3, H-FABP.

MCP-1: Monocyte chemotactic protein 1 is a chemokine secreted by immune cells. It recruits monocytes and is thought to be a marker of inflammation. Synonyms: C-C motif chemokine 2.

neurogranin: a dendritic protein implicated in synaptic plasticity. CSF neurogranin is thought to reflect synaptic degeneration.

NFL: Neurofilament light polypeptide is an intermediate filament protein found in the cytoskeleton of neurons.

NSE: Neuron-specific enolase is a glycolytic enzyme enriched in neurons. Synonyms: Enolase 2, Gamma-enolase.

sAPPα: soluble Amyloid precursor protein alpha is a secreted cleavage product of Amyloid Precursor Protein (APP). Synonyms: secreted amyloid precursor protein alpha.

sAPPβ: soluble Amyloid precursor protein beta is a secreted cleavage product of Amyloid Precursor Protein (APP). Synonyms: secreted amyloid precursor protein beta.

sTREM2: soluble Triggering receptor expressed on myeloid cells 2 (sTREM2) is an ectodomain fragment released by the proteolytic processing of the microglial transmembrane protein.

tau-p181: tau phosphorylated at threonine 181.

tau-p217: tau phosphorylated at threonine 217.

tau-p231: tau phosphorylated at threonine 231.

tau-total: total tau protein irrespective of phosphorylation state. Synonyms: microtubule-associated protein tau.

VLP-1: Visinin-like protein 1 is a neuronal calcium signaling molecule. Synonyms: VILIP-1, Hippocalcin-like protein 3.

YKL-40: Chitinase-3-like protein 1 is a glycoprotein that structurally resembles chitotriosidase and is mainly expressed in astrocytes in the brain. It is thought to be a marker of neuroinflammation.

α-synuclein: a pre-synaptic protein that accumulates into Lewy bodies and Lewy neurites in Parkinson’s disease, dementia with Lewy bodies, and multiple system atrophy.

Conditions

Alzheimer's Disease (AD): Clinical Alzheimer's disease as defined by specified diagnostic criteria.

Amyotrophic Lateral Sclerosis (ALS): Clinical amyotrophic lateral sclerosis as defined by specified diagnostic criteria.

Cerebral Amyloid Angiopathy (CAA): Cerebral amyloid angiopathy as defined by specified diagnostic criteria, which include clinical history with biopsy, imaging, or histopathological evidence.

Controls: Cognitively Normal Control (CNC): A control group reported by the authors to be cognitively healthy, with or without neuropsychiatric testing.

Controls: Other Controls: Individuals described as "hospital controls" and those with non-neurodegenerative diseases. Cognitive status is often unknown or not reported.

Controls: Subjective Cognitive Impairment (SCI): Subjects with self-reported cognitive complaints who score within normal ranges on neuropsychiatric tests.

Corticobasal Syndrome (CBS): A clinical syndrome defined by extrapyramidal (motor) and cortical signs and symptoms. While the term corticobasal degeneration (CBD) has been used interchangeably with CBS, particularly in earlier studies, we reserved the designation of CBD for a neuropathologically-confirmed 4R tauopathy with particular cellular features (e.g., tau-positive astrocytic inclusions) in specific brain regions. Therefore, for the Alzbiomarker meta-analyses, subjects were classified as CBS even in cases where the authors of a study had categorized them as CBD if only clinical criteria—absent neuropathology—were used for diagnosis.

Creutzfeldt-Jakob Disease, Genetic (gCJD): A human prion disease characterized by rapidly progressing dementia and defined by specified diagnostic criteria. The genetic form of the disease is caused by mutations in PRPN, the gene encoding the prion protein. As of this writing, the gCJD cases in Alzbiomarker all carried the p.Glu200Lys mutation. For the Alzbiomarker meta-analyses, the sporadic form of the disease was analyzed separately from the genetic form.

Creutzfeldt-Jakob Disease, Sporadic (sCJD): A human prion disease characterized by rapidly progressing dementia and defined by specified diagnostic criteria. For the Alzbiomarker meta-analyses, the sporadic form of the disease was analyzed separately from the genetic form.

Depression (DEP): Depression, as defined by specified diagnostic criteria. This category includes, but is not limited to, major depressive disorder.

Dementia with Lewy Bodies (DLB): Dementia with Lewy bodies as defined by specified clinical or neuropathological criteria. DLB, like Parkinson’s disease dementia (PDD), is marked by the presence of α-synuclein-positive inclusions called Lewy bodies. The two conditions differ in the order of appearance of signs and symptoms, with dementia preceding motor dysfunction in DLB, while motor symptoms appear first in PDD.

Fatal Familial Insomnia (FFI): The prion disease fatal familial insomnia, confirmed by genetic testing.

Frontotemporal Dementia (FTD):  A spectrum of clinical syndromes associated with atrophy of the frontal and anterior temporal lobes, also referred to as frontotemporal lobar degeneration (FTLD). These syndromes encompass behavioral, language, cognitive, and motor disorders and are defined by specified diagnostic criteria. For the Alzbiomarker meta-analyses, the following types of FTD were meta-analyzed together: behavioral variant FTD (bvFTD), non-fluent/agrammatic variant primary progressive aphasia (avPPA/nfvPPA), semantic variant primary progressive aphasia (svPPA), FTD with Parkinsonism (FTD-Parkinsonism), and “frontotemporal dementia” as designated by study authors, without further sub-classification. Also included in the FTD meta-analyses were data from subjects classified by study authors as FTLD-tau or FTLD-TDP43. Depending on the study, FTLD-TDP43 was defined by neuropathological findings at autopsy or the presence of mutations in GRN or C9ORF72, while FTLD-tau was defined by autopsy findings, MAPT mutations, or clinical syndromes related to tau pathology—FTLD-progressive supranuclear palsy and FTLD-corticobasal syndrome. (Note that, for the Alzbiomarker meta-analyses, corticobasal syndrome and progressive supranuclear palsy were meta-analyzed separately, with the exception of cases where study authors included these syndromes under FTLD-tau.)

Logopenic Variant Primary Progressive Aphasia (lvPPA): A language impairment defined by specified diagnostic criteria; a core feature is difficulty in word finding. In contrast to avPPA/nfvPPA and svPPA, which are associated with tau and TDP43 pathology and are classified as forms of frontotemporal dementia, lvPPA is more frequently associated with amyloid pathology.

Mild Cognitive Impairment Progressing to Alzheimer's disease (MCI-AD): Individuals meeting criteria for mild cognitive impairment at baseline who convert to a diagnosis of Alzheimer's dementia at a later clinical evaluation.

Mild Cognitive Impairment, Stable (MCI-stable): Individuals meeting criteria for mild cognitive impairment at baseline who maintain MCI status at clinical evaluation at least two years later.

Multiple System Atrophy (MSA): A synucleinopathy defined by specified diagnostic criteria, including autonomic dysfunction plus parkinsonism (“MSA-P”) or cerebellar ataxia (“MSA-C”). The two forms of MSA are meta-analyzed together in Alzbiomarker.

Normal Pressure Hydrocephalus (NPH): A buildup of cerebrospinal fluid leading to an expansion of the cerebral ventricles without an increase in intracranial pressure.

Posterior Cortical Atrophy (PCA): A condition characterized by progressive visual impairments of cortical origin, defined by specified diagnostic criteria. The signs and symptoms of PCA are most commonly associated with Alzheimer’s pathology, but the clinical syndrome has also been associated with Creutzfeldt-Jakob disease and dementia with Lewy bodies.

Parkinson’s Disease (PD): A progressive movement disorder associated with the loss of dopaminergic neurons and the presence of α-synuclein-positive inclusions called Lewy bodies. Although the vast majority of studies meta-analyzed in Alzbiomarker reported the published criteria used for diagnosis, this was not a requirement for inclusion.

Parkinson’s Disease Dementia (PDD): Parkinson’s disease dementia (PDD) as defined by specified diagnostic criteria. PDD, like dementia with Lewy bodies (DLB), is marked by the presence of α-synuclein-positive inclusions called Lewy bodies. The two conditions differ in the order of appearance of signs and symptoms: In PDD, the onset of dementia occurs many years after the motor symptoms of Parkinson’s disease, while dementia precedes motor dysfunction in DLB.

Progressive Supranuclear Palsy (PSP): Progressive supranuclear palsy (PSP) as defined by specified diagnostic criteria. Clinical signs include gaze abnormalities, postural instability, falls, and cognitive dysfunction. Neuropathologically, PSP is a 4R tauopathy with neurodegeneration primarily in the brainstem.

Vascular Dementia (VaD):  Vascular dementia (VaD), dementia due to impaired blood flow to the brain, as defined by specified diagnostic criteria.

Methods

Alpha-LISA: A bead-based assay performed in a microplate. "Alpha" is an acronym for amplified luminescent proximity homogeneous assay. In this assay, a light signal is generated by energy transfer from a donor bead to an acceptor bead when the beads are in close proximity. In addition to the chemical entities responsible for generating the light signal, the donor and acceptor beads carry antibodies directed against non-overlapping epitopes on the target analyte. The donor and acceptor beads are brought together when these antibodies bind a common analyte molecule.

Biochip Immunoassay:An immunoassay using a chip format to simultaneously measure multiple analytes in a single sample. The chip is divided into discrete regions, each specialized for the detection of a particular target analyte. For example, one version is an array of miniaturized sandwich ELISAs, where each region contains a capture antibody directed against a different analyte.

Colorimetric Assay: An assay using reagents that undergo a measurable color change in the presence of the analyte. The color change correlates with the concentration of the analyte.

Electrochemiluminescence: An immunoassay using detection antibodies associated with an electrochemiluminescent label.  Light is emitted when an electric current is applied in an appropriate buffer solution.

ELISA: A common protein analysis technique, usually conducted in a 96-well plate format, in which the antigen is stabilized on a solid surface and probed with a specific enzyme-conjugated antibody. The resulting enzymatic reaction is then measured. Traditional ELISAs use chromogenic reporters. Newer ELISA techniques use fluorogenic and electrochemiluminescent reporters which can offer higher sensitivities and the ability to simultaneously detect multiple antigens (i.e., multiplex). Although not technically ELISA, because they are not "enzyme-linked", these assays are often called ELISA due to similarities in the general assay principles. In sandwich ELISAs, a capture antibody is used to immobilize the target analyte/antigen on the solid surface.

Fully Automated Immunoassay: Immunoassay in which reagent exchanges are performed by machines, with the goal of decreasing variability inherent in manual liquid handling procedures.

Immunoelectrophoresis: A type of immunodiffusion technique in which a mixed protein sample is first separated by gel electrophoresis and then the individual proteins are visualized by applying specific antibodies to the gel through immunodiffusion. When levels of antigen and antibody are near equivalent, the complexes that form precipitate and are detectable as a precipitin arc.

Immunomagnetic Reduction: An immunoassay in which magnetic particles are coated with antibody and the reduction in the spin of the particles correlates with the amount of ligand bound.

Mass Spectrometry: A sensitive technique used to detect, identify, and quantify molecules based on their mass and charge (m/z) ratio.

Nephelometry: A technique to assess protein levels, by measuring the turbidity of a sample. Typically an antibody and antigen are mixed and the resulting small aggregates are detected by passing a light through the sample. The amount of light scatter is compared to a standard curve.

Radio Immunoassay (RIA): A classic quantitative immunoassay technique that uses antibodies to detect and quantitate the amount of antigen in a sample. Typically  radioactive isotopes, such as 125I or 3H, are used to label an antigen (known as a tracer or radioligand), which then competes with a non-radioactive antigen for a fixed number of antibody or receptor binding sites. Results are compared against a standard curve.

SIMOA (Single Molecule Array): A bead-based immunoassay in which a target analyte is captured by antibody-coated beads and then detected using an enzyme-labeled detection antibody. The detection reaction is compartmentalized in femtoliter microwells, which may allow for a single-molecule analyte readout.

Single Molecule Counting Immunoassay: A highly sensitive immunoassay capable of detecting single fluorescent antibodies. At its initial stages, the assay resembles a sandwich ELISA in a plate-based or bead-based format. However, after binding to the target analyte, the fluorescently labeled detection antibody is eluted from the reaction complex. In the Erenna system, the solution containing the eluted detection antibody is flowed past a laser and the fluorescence signal is quantified.

Surface Plasmon Resonance: An optical detection technique used to study molecular interactions, in this case the binding of antibody to antigen. Light hitting a metal surface at a particular angle causes electrons in the metal (“surface plasmons”) to resonate.  This electron resonance results in a loss of intensity of the light reflected from the surface. The SPR signal—the intensity of the reflected light—is very sensitive to molecules bound to the metal’s surface. In practice, antibodies are immobilized on a thin metal film and the solution containing the analyte is made to flow over the film, while the SPR signal is monitored; binding of target analyte to antibody results in a change in the SPR signal. Notably, this is a label-free method— neither the analytes nor the antibodies are tagged.

SRM (Selected Reaction Monitoring): A targetted mass spectrometry technique for the detection and quantification of specific predetermined analytes with known fragmentation properties.

Turbidimetry:A technique to assess protein levels, by measuring the cloudiness (“turbidity”) of a sample. Typically, an antibody and antigen are mixed and the resulting small aggregates are detected by passing a light through the sample. The amount of light transmitted depends on the concentration of particles in the solution and is compared to a standard curve. This technique is very similar to nephelometry, where the amount of scattered light—rather than transmitted light—is measured.

xMAP: A bead-based multiplex immunoassay patented by the Luminex Corporation that allows for the detection of multiple analytes in a sample through the use of antibody-labeled microspheres with different spectral properties. Synonyms: xMAP (multi-analyte profiling).

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