The clinical promise of biomarkers of synapse damage or loss in Alzheimer’s disease

Colom‐Cadena, Martí; Spires‐Jones, Tara L.; Zetterberg, Henrik; Blennow, Kaj; Caggiano, Anthony O.; DeKosky, Steven T.; Fillit, Howard; Harrison, John; Schneider, Lon S.; Scheltens, Philip; Haan, Willem de; Grundman, Michael; Dyck, Christopher H. van; Izzo, Nicholas J.; Catalano, Susan M.

doi:10.1186/s13195-020-00588-4

Cited by 225 publications

(186 citation statements)

References 162 publications

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“…In our assessment of disease biomarkers, we focused on a small set of markers with the best-established association with the prion disease process. Future analyses could explore other emerging biomarkers of neurodegeneration, such as synaptic proteins [69,70]. Table 2 Comparison of visits for one RT-QuIC-positive study participant.…”

Section: Discussionmentioning

confidence: 99%

Cerebrospinal fluid and plasma biomarkers in individuals at risk for genetic prion disease

Vallabh

Minikel

Williams

et al. 2020

BMC Med

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Background: Prion disease is neurodegenerative disease that is typically fatal within months of first symptoms. Clinical trials in this rapidly declining symptomatic patient population have proven challenging. Individuals at high lifetime risk for genetic prion disease can be identified decades before symptom onset and provide an opportunity for early therapeutic intervention. However, randomizing pre-symptomatic carriers to a clinical endpoint is not numerically feasible. We therefore launched a cohort study in pre-symptomatic genetic prion disease mutation carriers and controls with the goal of evaluating biomarker endpoints that may enable informative trials in this population. Methods: We collected cerebrospinal fluid (CSF) and blood from pre-symptomatic individuals with prion protein gene (PRNP) mutations (N = 27) and matched controls (N = 16), in a cohort study at Massachusetts General Hospital. We quantified total prion protein (PrP) and real-time quaking-induced conversion (RT-QuIC) prion seeding activity in CSF and neuronal damage markers total tau (T-tau) and neurofilament light chain (NfL) in CSF and plasma. We compared these markers cross-sectionally, evaluated short-term test-retest reliability over 2-4 months, and conducted a pilot longitudinal study over 10-20 months. Results: CSF PrP levels were stable on test-retest with a mean coefficient of variation of 7% for both over 2-4 months in N = 29 participants and over 10-20 months in N = 10 participants. RT-QuIC was negative in 22/23 mutation carriers. The sole individual with positive RT-QuIC seeding activity at two study visits had steady CSF PrP levels and slightly increased tau and NfL concentrations compared with the others, though still within the normal range, and remained asymptomatic 1 year later. T-tau and NfL showed no significant differences between mutation carriers and controls in either CSF or plasma.

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Section: Discussionmentioning

confidence: 99%

Cerebrospinal fluid and plasma biomarkers in individuals at risk for genetic prion disease

Vallabh

Minikel

Williams

et al. 2020

BMC Med

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“…However, most studies identified the oligomeric forms of Aβ and tau, rather than larger aggregates, to be the synaptotoxic species. 45 - 49 Both in vivo 50 and ex vivo 51 Aβ oligomers (Aβo) disrupt LTP, probably interfering with NMDAR ( N -methyl- d -aspartate receptor) activity and downstream pathways, 52 in addition to causing oxidative stress, impairing axonal transport, and causing nerve cell death (reviewed in Cline et al 53 ). In AD, Aβ and tau act in concert and studies have identified their simultaneous presence in the postsynaptic compartment.…”

Section: Pathophysiology Of Synaptic Dysfunction and Lossmentioning

confidence: 99%

Fluid Biomarkers for Synaptic Dysfunction and Loss

et al. 2020

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Synapses are the site for brain communication where information is transmitted between neurons and stored for memory formation. Synaptic degeneration is a global and early pathogenic event in neurodegenerative disorders with reduced levels of pre- and postsynaptic proteins being recognized as a core feature of Alzheimer’s disease (AD) pathophysiology. Together with AD, other neurodegenerative and neurodevelopmental disorders show altered synaptic homeostasis as an important pathogenic event, and due to that, they are commonly referred to as synaptopathies. The exact mechanisms of synapse dysfunction in the different diseases are not well understood and their study would help understanding the pathogenic role of synaptic degeneration, as well as differences and commonalities among them and highlight candidate synaptic biomarkers for specific disorders. The assessment of synaptic proteins in cerebrospinal fluid (CSF), which can reflect synaptic dysfunction in patients with cognitive disorders, is a keen area of interest. Substantial research efforts are now directed toward the investigation of CSF synaptic pathology to improve the diagnosis of neurodegenerative disorders at an early stage as well as to monitor clinical progression. In this review, we will first summarize the pathological events that lead to synapse loss and then discuss the available data on established (eg, neurogranin, SNAP-25, synaptotagmin-1, GAP-43, and α-syn) and emerging (eg, synaptic vesicle glycoprotein 2A and neuronal pentraxins) CSF biomarkers for synapse dysfunction, while highlighting possible utilities, disease specificity, and technical challenges for their detection.

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“…The presence of amyloid beta oligomer (AβO) has been correlated with synaptic plasticity impairment and frank synapse loss in mice and cell models [20][21][22][23] and in human brains in AD [24,25]. The cognitive impairment in AD closely parallels the loss of synapses due to the toxic effects of Aβ, tau, and inflammation; thus, emerging biomarkers are able to measure synapse injury and loss in the brain and may correlate with cognitive function in AD [26].…”

Section: Biomarkers In Alzheimer's Diseasementioning

confidence: 99%

Role of Body-Fluid Biomarkers in Alzheimer’s Disease Diagnosis

Nguyen

et al. 2020

Diagnostics

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Alzheimer’s disease (AD) is a complex neurodegenerative disease that requires extremely specific biomarkers for its diagnosis. For current diagnostics capable of identifying AD, the development and validation of early stage biomarkers is a top research priority. Body-fluid biomarkers might closely reflect synaptic dysfunction in the brain and, thereby, could contribute to improving diagnostic accuracy and monitoring disease progression, and serve as markers for assessing the response to disease-modifying therapies at early onset. Here, we highlight current advances in the research on the capabilities of body-fluid biomarkers and their role in AD pathology. Then, we describe and discuss current applications of the potential biomarkers in clinical diagnostics in AD.

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The clinical promise of biomarkers of synapse damage or loss in Alzheimer’s disease

Cited by 225 publications

References 162 publications

Cerebrospinal fluid and plasma biomarkers in individuals at risk for genetic prion disease

Cerebrospinal fluid and plasma biomarkers in individuals at risk for genetic prion disease

Fluid Biomarkers for Synaptic Dysfunction and Loss

Role of Body-Fluid Biomarkers in Alzheimer’s Disease Diagnosis

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