Novel CSF biomarkers in genetic frontotemporal dementia identified by proteomics.

OBJECTIVE: To identify novel CSF biomarkers in GRN-associated frontotemporal dementia (FTD) by proteomics using mass spectrometry (MS). METHODS: Unbiased MS was applied to CSF samples from 19 presymptomatic and 9 symptomatic GRN mutation carriers and 24 noncarriers. Protein abundances were compared between these groups. Proteins were then selected for validation if identified by ≥4 peptides and if fold change was ≤0.5 or ≥2.0. Validation and absolute quantification by parallel reaction monitoring (PRM), a high-resolution targeted MS method, was performed on an international cohort (n = 210) of presymptomatic and symptomatic GRN, C9orf72 and MAPT mutation carriers. RESULTS: Unbiased MS revealed 20 differentially abundant proteins between symptomatic mutation carriers and noncarriers and nine between symptomatic and presymptomatic carriers. Seven of these proteins fulfilled our criteria for validation. PRM analyses revealed that symptomatic GRN mutation carriers had significantly lower levels of neuronal pentraxin receptor (NPTXR), receptor-type tyrosine-protein phosphatase N2 (PTPRN2), neurosecretory protein VGF, chromogranin-A (CHGA), and V-set and transmembrane domain-containing protein 2B (VSTM2B) than presymptomatic carriers and noncarriers. Symptomatic C9orf72 mutation carriers had lower levels of NPTXR, PTPRN2, CHGA, and VSTM2B than noncarriers, while symptomatic MAPT mutation carriers had lower levels of NPTXR and CHGA than noncarriers. INTERPRETATION: We identified and validated five novel CSF biomarkers in GRN-associated FTD. Our results show that synaptic, secretory vesicle, and inflammatory proteins are dysregulated in the symptomatic stage and may provide new insights into the pathophysiology of genetic FTD. Further validation is needed to investigate their clinical applicability as diagnostic or monitoring biomarkers.

Cerebrospinal Fluid TAR DNA-Binding Protein 43 Combined with Tau Proteins as a Candidate Biomarker for Amyotrophic Lateral Sclerosis and Frontotemporal Dementia Spectrum Disorders.

BACKGROUND: Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are nowadays recognized as spectrum disorders with a molecular link, the TAR DNA-binding protein 43 (TDP-43), rendering it a surrogate biomarker for these disorders. METHODS: We measured cerebrospinal fluid (CSF) levels of TDP-43, beta-amyloid peptide with 42 amino acids (Aß42), total tau protein (τT), and tau protein phosphorylated at threonine 181 (τP-181) in 32 patients with ALS, 51 patients with FTD, and 17 healthy controls. Double-sandwich commercial enzyme-linked immunosorbent assays were used for measurements. RESULTS: Both ALS and FTD patients presented with higher TDP-43 and τT levels compared to the control group. The combination of biomarkers in the form of the TDP-43 × τT / τP-181 formula achieved the best discrimination between ALS or FTD and controls, with sensitivities and specificities >0.8. CONCLUSION: Combined analysis of TDP-43, τT, and τP-181 in CSF may be useful for the antemortem diagnosis of ALS and FTD.

Ultrasensitive and selective detection of 3-repeat tau seeding activity in Pick disease brain and cerebrospinal fluid.

The diagnosis and treatment of diseases involving tau-based pathology such as Alzheimer disease and certain frontotemporal dementias is hampered by the inability to detect pathological forms of tau with sufficient sensitivity, specificity and practicality. In these neurodegenerative diseases, tau accumulates in self-seeding filaments. For example, Pick disease (PiD) is associated with frontotemporal degeneration and accumulation of 3-repeat (3R) tau isoforms in filaments constituting Pick bodies. Exploiting the self-seeding activity of tau deposits, and using a 3R tau fragment as a substrate, we have developed an assay (tau RT-QuIC) that can detect tau seeds in 2 µl aliquots of PiD brain dilutions down to 10-7-10-9. PiD seeding activities were 100-fold higher in frontal and temporal lobes compared to cerebellar cortex. Strikingly, this test was 103- to 105-fold less responsive when seeded with brain containing predominant 4-repeat (4R) tau aggregates from cases of corticobasal degeneration, argyrophilic grain disease, and progressive supranuclear palsy. Alzheimer disease brain, with 3R + 4R tau deposits, also gave much weaker responses than PiD brain. When applied to cerebrospinal fluid samples (5 µl), tau RT-QuIC analyses discriminated PiD from non-PiD cases. These findings demonstrate that abnormal tau aggregates can be detected with high sensitivity and disease-specificity in crude tissue and fluid samples. Accordingly, this tau RT-QuIC assay exemplifies a new approach to diagnosing tauopathies and monitoring therapeutic trials using aggregated tau itself as a biomarker.

Decreased cerebrospinal fluid Abeta(42) correlates with brain atrophy in cognitively normal elderly.

OBJECTIVE: For therapies for Alzheimer's disease (AD) to have the greatest impact, it will likely be necessary to treat individuals in the "preclinical" (presymptomatic) stage. Fluid and neuroimaging measures are being explored as possible biomarkers of AD pathology that could aid in identifying individuals in this stage to target them for clinical trials and to direct and monitor therapy. The objective of this study was to determine whether cerebrospinal fluid (CSF) biomarkers for AD suggest the presence of brain damage in the preclinical stage of AD. METHODS: We investigated the relation between structural neuroimaging measures (whole-brain volume) and levels of CSF amyloid-beta (Abeta)(40), Abeta(42), tau, and phosphorylated tau(181) (ptau(181)), and plasma Abeta(40) and Abeta(42) in well-characterized research subjects with very mild and mild dementia of the Alzheimer type (n = 29) and age-matched, cognitively normal control subjects (n = 69). RESULTS: Levels of CSF tau and ptau(181), but not Abeta(42), correlated inversely with whole-brain volume in very mild and mild dementia of the Alzheimer type, whereas levels of CSF Abeta(42), but not tau or ptau(181), were positively correlated with whole-brain volume in nondemented control subjects. INTERPRETATION: Reduction in CSF Abeta(42), likely reflecting Abeta aggregation in the brain, is associated with brain atrophy in the preclinical phase of AD. This suggests that there is toxicity associated with Abeta aggregation before the onset of clinically detectable disease. Increases in CSF tau (and ptau(181)) are later events that correlate with further structural damage and occur with clinical onset and progression.

The cerebrospinal fluid levels of tau, growth-associated protein-43 and soluble amyloid precursor protein correlate in Alzheimer's disease, reflecting a common pathophysiological process.

Cerebrospinal fluid (CSF) levels of tau (total tau), growth-associated protein-43 (GAP-43), soluble amyloid precursor protein (sAPP; i.e. total sAPP), and beta-amyloid(42) (Abeta(42)) were studied in patients with frontotemporal dementia (FTD; n = 14), Alzheimer's disease (AD; n = 47) and vascular dementia (VAD; n = 16), and in age-matched controls (n = 12). CSF-tau was increased in AD compared to controls and FTD (p < 0.001 for both). CSF-GAP-43 was increased in AD compared to controls (p < 0.05), and both CSF-GAP-43 and CSF-sAPP were increased in AD compared to FTD (p < 0.01). Positive and highly significant correlations were found between CSF-tau and CSF-GAP-43 in all groups and between CSF-tau, CSF-GAP-43 and CSF-sAPP in AD. The correlations found may reflect a common pathophysiologic process such as axonal degeneration.